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Conserved domains on  [gi|1862756640|ref|NP_001371815|]
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signal transducer and activator of transcription 1-alpha/beta isoform 7 [Homo sapiens]

Protein Classification

SH2 domain-containing protein; tyrosine-protein kinase( domain architecture ID 13929417)

SH2 (Src homology 2) domain-containing protein may act as an intracellular signal-transducing protein; tyrosine-protein kinase catalyzes the autophosphorylation on a C-terminal tyrosine cluster and also phosphorylates endogenous protein substrates by using ATP as the phosphoryl donor

Graphical summary

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List of domain hits

Name Accession Description Interval E-value
STAT1_DBD cd16845
DNA-binding domain of Signal Transducer and Activator of Transcription 1 (STAT1); This family ...
317-477 9.08e-110

DNA-binding domain of Signal Transducer and Activator of Transcription 1 (STAT1); This family consists of the DNA-binding domain (DBD) of the STAT1 proteins (Signal Transducer and Activator of Transcription 1, or Signal Transduction And Transcription 1). The DNA binding domain has an Ig-like fold. STAT1 plays an essential role in mediating responses to all types of interferons (IFN), transducing signals from cytoplasmic domains of transmembrane receptors into the nucleus where it regulates gene expression. Thus STAT1 is involved in modulating diverse cellular processes, such as antimicrobial activities, cell proliferation and cell death. STAT1 function is crucial in the innate and adaptive arm of immunity and protects from pathogen infections; phosphorylation of a critical tyrosine by Janus kinases (JAKs) leads to its activation and nuclear translocation, while phosphorylation of a critical serine is required for full transcriptional activation upon IFN stimulation and in response to cellular stress. Transcription of protein-encoding genes (including Stat1 itself) as well as expression of microRNAs (miRNAs) is regulated by activated STAT1. Animal studies have shown that STAT1 is generally considered a tumor suppressor but it can also act as a tumor promoter; its functions are not restricted to tumor cells, but extend to parts of the tumor microenvironment such as immune cells, endothelial cells. STAT1 abundance is a reliable marker for good prognosis in selected tumor types, but it can also correlate with disease progression. In head and neck cancer (HNC) patients, upregulation of STAT1-induced HLA class I enhances immunogenicity and clinical response to anti-EGFR mAb cetuximab therapy. In systemic juvenile idiopathic arthritis (sJIA) characterized by systemic inflammation and arthritis, STAT1 phosphorylation downstream of IFNs is impaired. It exerts anti-oncogenic activities through interferon-gamma and interferon-alpha. STAT1 may inhibit hepatocellular carcinoma cell growth by regulating p53-related cell cycling and apoptosis. Studies also show a significant correlation of high STAT1 activity with longer colorectal cancer patient overall survival. Recent studies have shown that STAT1 suppresses mouse mammary gland tumorigenesis by immune regulatory as well as tumor cell-specific functions of STAT1.


:

Pssm-ID: 341083  Cd Length: 161  Bit Score: 330.68  E-value: 9.08e-110
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 317 FVVERQPCMPTHPQRPLVLKTGVQFTVKLRLLVKLQELNYNLKVKVLFDKDVNERNTVKGFRKFNILGTHTKVMNMEEST 396
Cdd:cd16845     1 FVVERQPCMPTHPQRPLVLKTGVQFTVKLRLLVKLQELNYQLKVKVLFDKDVTEKNTVKGFRKFNILGTNTKVMNMEEST 80
                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 397 NGSLAAEFRHLQLKEQKNAGTRTNEGPLIVTEELHSLSFETQLCQPGLVIDLETTSLPVVVISNVSQLPSGWASILWYNM 476
Cdd:cd16845    81 NGSLAAEFRHLQLKEQKNAGTRTNEGPLIVTEELHSLSFETQLCQPGLVIDLETTSLPIVVISNVSQLPSGWASILWYNM 160

                  .
gi 1862756640 477 L 477
Cdd:cd16845   161 L 161
SH2_STAT1 cd10372
Src homology 2 (SH2) domain found in signal transducer and activator of transcription (STAT) 1 ...
557-715 2.68e-105

Src homology 2 (SH2) domain found in signal transducer and activator of transcription (STAT) 1 proteins; STAT1 is a member of the STAT family of transcription factors. STAT1 is involved in upregulating genes due to a signal by interferons. STAT1 forms homodimers or heterodimers with STAT3 that bind to the Interferon-Gamma Activated Sequence (GAS) promoter element in response to IFN-gamma stimulation. STAT1 forms a heterodimer with STAT2 that can bind Interferon Stimulated Response Element (ISRE) promoter element in response to either IFN-alpha or IFN-beta stimulation. Binding in both cases leads to an increased expression of ISG (Interferon Stimulated Genes). STAT1 has been shown to interact with protein kinase R, Src, IRF1, STAT3, MCM5, STAT2, CD117, Fanconi anemia, complementation group C, CREB-binding protein, Interleukin 27 receptor, alpha subunit, PIAS1, BRCA1, Epidermal growth factor receptor, PTK2, Mammalian target of rapamycin, IFNAR2, PRKCD, TRADD, C-jun, Calcitriol receptor, ISGF3G, and GNB2L1. STAT proteins mediate the signaling of cytokines and a number of growth factors from the receptors of these extracellular signaling molecules to the cell nucleus. STATs are specifically phosphorylated by receptor-associated Janus kinases, receptor tyrosine kinases, or cytoplasmic tyrosine kinases. The phosphorylated STAT molecules dimerize by reciprocal binding of their SH2 domains to the phosphotyrosine residues. These dimeric STATs translocate into the nucleus, bind to specific DNA sequences, and regulate the transcription of their target genes. However there are a number of unphosphorylated STATs that travel between the cytoplasm and nucleus and some STATs that exist as dimers in unstimulated cells that can exert biological functions independent of being activated. There are seven mammalian STAT family members which have been identified: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6. There are 6 conserved domains in STAT: N-terminal domain (NTD), coiled-coil domain (CCD), DNA-binding domain (DBD), alpha-helical linker domain (LD), SH2 domain, and transactivation domain (TAD). NTD is involved in dimerization of unphosphorylated STATs monomers and for the tetramerization between STAT1, STAT3, STAT4 and STAT5 on promoters with two or more tandem STAT binding sites. It also plays a role in promoting interactions with transcriptional co-activators such as CREB binding protein (CBP)/p300, as well as being important for nuclear import and deactivation of STATs involving tyrosine de-phosphorylation. CCD interacts with other proteins, such as IFN regulatory protein 9 (IRF-9/p48) with STAT1 and c-JUN with STAT3 and is also thought to participate in the negative regulation of these proteins. Distinct genes are bound to STATs via their DBD domain. This domain is also involved in nuclear translocation of activated STAT1 and STAT3 phosphorylated dimers upon cytokine stimulation. LD links the DNA-binding and SH2 domains and is important for the transcriptional activation of STAT1 in response to IFN-gamma. It also plays a role in protein-protein interactions and has also been implicated in the constitutive nucleocytoplasmic shuttling of unphosphorylated STATs in resting cells. The SH2 domain is necessary for receptor association and tyrosine phosphodimer formation. Residues within this domain may be particularly important for some cellular functions mediated by the STATs as well as residues adjacent to this domain. The TAD interacts with several proteins, namely minichromosome maintenance complex component 5 (MCM5), breast cancer 1 (BRCA1) and CBP/p300. TAD also contains a modulatory phosphorylation site that regulates STAT activity and is necessary for maximal transcription of a number of target genes. The conserved tyrosine residue present in the C-terminus is crucial for dimerization via interaction with the SH2 domain upon the interaction of the ligand with the receptor. STAT activation by tyrosine phosphorylation also determines nuclear import and retention, DNA binding to specific DNA elements in the promoters of responsive genes, and transcriptional activation of STAT dimers. In addition to the SH2 domain there is a coiled-coil domain, a DNA binding domain, and a transactivation domain in the STAT proteins. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


:

Pssm-ID: 198235  Cd Length: 151  Bit Score: 318.77  E-value: 2.68e-105
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 557 WIESILELIKKHLLPLWNDGCIMGFISKERERALLKDQQPGTFLLRFSESSREGAITFTWVERSQNGGEPDFHAVEPYTK 636
Cdd:cd10372     1 WIESILELIKKHLLSLWNDGCIMGFISKERERALLKDQQPGTFLLRFSESSREGAITFTWVERSQNGGEPDFHAVEPYTK 80
                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1862756640 637 KELSAVTFPDIIRNYKVMAAENIPENPLKYLYPNIDKDHAFGKYYSRPKEaytmclflAPEPMELDGPKGTGYIKTELI 715
Cdd:cd10372    81 KELSAVTFPDIIRNYKVMAAENIPENPLKYLYPNIDKDHAFGKYYSRPKE--------APEPMELDGPKGTGYIKTELI 151
STAT1_CCD cd16851
Coiled-coil domain of Signal Transducer and Activator of Transcription 1 (STAT1); This family ...
138-313 1.17e-104

Coiled-coil domain of Signal Transducer and Activator of Transcription 1 (STAT1); This family consists of the coiled-coil (alpha) domain of the STAT1 proteins (Signal Transducer and Activator of Transcription 1, or Signal Transduction And Transcription 1). STAT1 plays an essential role in mediating responses to all types of interferons (IFN), transducing signals from cytoplasmic domains of transmembrane receptors into the nucleus where it regulates gene expression. Thus STAT1 is involved in modulating diverse cellular processes, such as antimicrobial activities, cell proliferation and cell death. STAT1 function is crucial in the innate and adaptive arm of immunity and protects from pathogen infections; phosphorylation of a critical tyrosine by Janus kinases (JAKs) leads to its activation and nuclear translocation, while phosphorylation of a critical serine is required for full transcriptional activation upon IFN stimulation and in response to cellular stress. Transcription of protein-encoding genes (including Stat1 itself) as well as expression of microRNAs (miRNAs) is regulated by activated STAT1. Animal studies have shown that STAT1 is generally considered a tumor suppressor but it can also act as a tumor promoter; its functions are not restricted to tumor cells, but extend to parts of the tumor microenvironment such as immune cells, endothelial cells. STAT1 abundance is a reliable marker for good prognosis in selected tumor types, but it can also correlate with disease progression. In head and neck cancer (HNC) patients, upregulation of STAT1-induced HLA class I enhances immunogenicity and clinical response to anti-EGFR mAb cetuximab therapy. In systemic juvenile idiopathic arthritis (sJIA) characterized by systemic inflammation and arthritis, STAT1 phosphorylation downstream of IFNs is impaired. It exerts anti-oncogenic activities through interferon-gamma and interferon-alpha. STAT1 may inhibit hepatocellular carcinoma cell growth by regulating p53-related cell cycling and apoptosis. Studies also show a significant correlation of high STAT1 activity with longer colorectal cancer patient overall survival. Recent studies have shown that STAT1 suppresses mouse mammary gland tumorigenesis by immune regulatory as well as tumor cell-specific functions of STAT1.


:

Pssm-ID: 341076  Cd Length: 176  Bit Score: 317.88  E-value: 1.17e-104
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 138 KQKELDSKVRNVKDKVMCIEHEIKSLEDLQDEYDFKCKTLQNREHETNGVAKSDQKQEQLLLKKMYLMLDNKRKEVVHKI 217
Cdd:cd16851     1 KQKELDAKVKDLKNSVQDAEQDIKSLEDLQDEYDFKRKTLQSREEETNGVAKEELKKEKLKLRKMFIKLKDKRKEVVHKI 80
                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 218 IELLNVTELTQNALINDELVEWKRRQQSACIGGPPNACLDQLQNWFTIVAESLQQVRQQLKKLEELEQKYTYEHDPITKN 297
Cdd:cd16851    81 IELLNVTELTQFALINDELVEWKRRQQMACIGGPPNACLDQLQNWFTIVAESLQQVRQQLKKLQELEQKLTYENDPITKN 160
                         170
                  ....*....|....*.
gi 1862756640 298 KQVLWDRTFSLFQQLI 313
Cdd:cd16851   161 KQALEERALSLFKNLI 176
STAT_int smart00964
STAT protein, protein interaction domain; STAT proteins (Signal Transducers and Activators of ...
2-121 5.78e-58

STAT protein, protein interaction domain; STAT proteins (Signal Transducers and Activators of Transcription) are a family of transcription factors that are specifically activated to regulate gene transcription when cells encounter cytokines and growth factors. STAT proteins also include an SH2 domain.


:

Pssm-ID: 214942  Cd Length: 120  Bit Score: 192.50  E-value: 5.78e-58
                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640    2 SQWYELQQLDSKFLEQVHQLYDDSFPMEIRQYLAQWLEKQDWEHAANDVSFATIRFHDLLSQLDDQYSRFSLENNFLLQH 81
Cdd:smart00964   1 SQWAQLQQLDSKFLEQVQQLYGDNFPMELRHYLADWIESQDWELAANDEAQATRLFHNLLEQLDQQLSRFSQESNFLLKH 80
                           90       100       110       120
                   ....*....|....*....|....*....|....*....|
gi 1862756640   82 NIRKSKRNLQDNFQEDPIQMSMIIYSCLKEERKILENAQR 121
Cdd:smart00964  81 NLRHIKSNLQSLYQENPLELARIIRNILQEERRILAEASR 120
STAT1_TAZ2bind pfam12162
STAT1 TAZ2 binding domain; This domain family is found in eukaryotes, and is approximately 20 ...
723-747 6.15e-05

STAT1 TAZ2 binding domain; This domain family is found in eukaryotes, and is approximately 20 amino acids in length, and the family is found in association with pfam02865, pfam00017, pfam01017, pfam02864. This domain is the C terminal domain of STAT1. This domain binds selectively to the TAZ2 domain of CRB (CREB-binding protein). In this process it becomes a transcriptional activator and can initiate transcription of certain genes.


:

Pssm-ID: 432372  Cd Length: 23  Bit Score: 40.45  E-value: 6.15e-05
                          10        20
                  ....*....|....*....|....*
gi 1862756640 723 SRLQttDNLLPMSPEEFDEVSRIVG 747
Cdd:pfam12162   1 SRLQ--ENLMPMSPEDYGELERMVR 23
 
Name Accession Description Interval E-value
STAT1_DBD cd16845
DNA-binding domain of Signal Transducer and Activator of Transcription 1 (STAT1); This family ...
317-477 9.08e-110

DNA-binding domain of Signal Transducer and Activator of Transcription 1 (STAT1); This family consists of the DNA-binding domain (DBD) of the STAT1 proteins (Signal Transducer and Activator of Transcription 1, or Signal Transduction And Transcription 1). The DNA binding domain has an Ig-like fold. STAT1 plays an essential role in mediating responses to all types of interferons (IFN), transducing signals from cytoplasmic domains of transmembrane receptors into the nucleus where it regulates gene expression. Thus STAT1 is involved in modulating diverse cellular processes, such as antimicrobial activities, cell proliferation and cell death. STAT1 function is crucial in the innate and adaptive arm of immunity and protects from pathogen infections; phosphorylation of a critical tyrosine by Janus kinases (JAKs) leads to its activation and nuclear translocation, while phosphorylation of a critical serine is required for full transcriptional activation upon IFN stimulation and in response to cellular stress. Transcription of protein-encoding genes (including Stat1 itself) as well as expression of microRNAs (miRNAs) is regulated by activated STAT1. Animal studies have shown that STAT1 is generally considered a tumor suppressor but it can also act as a tumor promoter; its functions are not restricted to tumor cells, but extend to parts of the tumor microenvironment such as immune cells, endothelial cells. STAT1 abundance is a reliable marker for good prognosis in selected tumor types, but it can also correlate with disease progression. In head and neck cancer (HNC) patients, upregulation of STAT1-induced HLA class I enhances immunogenicity and clinical response to anti-EGFR mAb cetuximab therapy. In systemic juvenile idiopathic arthritis (sJIA) characterized by systemic inflammation and arthritis, STAT1 phosphorylation downstream of IFNs is impaired. It exerts anti-oncogenic activities through interferon-gamma and interferon-alpha. STAT1 may inhibit hepatocellular carcinoma cell growth by regulating p53-related cell cycling and apoptosis. Studies also show a significant correlation of high STAT1 activity with longer colorectal cancer patient overall survival. Recent studies have shown that STAT1 suppresses mouse mammary gland tumorigenesis by immune regulatory as well as tumor cell-specific functions of STAT1.


Pssm-ID: 341083  Cd Length: 161  Bit Score: 330.68  E-value: 9.08e-110
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 317 FVVERQPCMPTHPQRPLVLKTGVQFTVKLRLLVKLQELNYNLKVKVLFDKDVNERNTVKGFRKFNILGTHTKVMNMEEST 396
Cdd:cd16845     1 FVVERQPCMPTHPQRPLVLKTGVQFTVKLRLLVKLQELNYQLKVKVLFDKDVTEKNTVKGFRKFNILGTNTKVMNMEEST 80
                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 397 NGSLAAEFRHLQLKEQKNAGTRTNEGPLIVTEELHSLSFETQLCQPGLVIDLETTSLPVVVISNVSQLPSGWASILWYNM 476
Cdd:cd16845    81 NGSLAAEFRHLQLKEQKNAGTRTNEGPLIVTEELHSLSFETQLCQPGLVIDLETTSLPIVVISNVSQLPSGWASILWYNM 160

                  .
gi 1862756640 477 L 477
Cdd:cd16845   161 L 161
SH2_STAT1 cd10372
Src homology 2 (SH2) domain found in signal transducer and activator of transcription (STAT) 1 ...
557-715 2.68e-105

Src homology 2 (SH2) domain found in signal transducer and activator of transcription (STAT) 1 proteins; STAT1 is a member of the STAT family of transcription factors. STAT1 is involved in upregulating genes due to a signal by interferons. STAT1 forms homodimers or heterodimers with STAT3 that bind to the Interferon-Gamma Activated Sequence (GAS) promoter element in response to IFN-gamma stimulation. STAT1 forms a heterodimer with STAT2 that can bind Interferon Stimulated Response Element (ISRE) promoter element in response to either IFN-alpha or IFN-beta stimulation. Binding in both cases leads to an increased expression of ISG (Interferon Stimulated Genes). STAT1 has been shown to interact with protein kinase R, Src, IRF1, STAT3, MCM5, STAT2, CD117, Fanconi anemia, complementation group C, CREB-binding protein, Interleukin 27 receptor, alpha subunit, PIAS1, BRCA1, Epidermal growth factor receptor, PTK2, Mammalian target of rapamycin, IFNAR2, PRKCD, TRADD, C-jun, Calcitriol receptor, ISGF3G, and GNB2L1. STAT proteins mediate the signaling of cytokines and a number of growth factors from the receptors of these extracellular signaling molecules to the cell nucleus. STATs are specifically phosphorylated by receptor-associated Janus kinases, receptor tyrosine kinases, or cytoplasmic tyrosine kinases. The phosphorylated STAT molecules dimerize by reciprocal binding of their SH2 domains to the phosphotyrosine residues. These dimeric STATs translocate into the nucleus, bind to specific DNA sequences, and regulate the transcription of their target genes. However there are a number of unphosphorylated STATs that travel between the cytoplasm and nucleus and some STATs that exist as dimers in unstimulated cells that can exert biological functions independent of being activated. There are seven mammalian STAT family members which have been identified: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6. There are 6 conserved domains in STAT: N-terminal domain (NTD), coiled-coil domain (CCD), DNA-binding domain (DBD), alpha-helical linker domain (LD), SH2 domain, and transactivation domain (TAD). NTD is involved in dimerization of unphosphorylated STATs monomers and for the tetramerization between STAT1, STAT3, STAT4 and STAT5 on promoters with two or more tandem STAT binding sites. It also plays a role in promoting interactions with transcriptional co-activators such as CREB binding protein (CBP)/p300, as well as being important for nuclear import and deactivation of STATs involving tyrosine de-phosphorylation. CCD interacts with other proteins, such as IFN regulatory protein 9 (IRF-9/p48) with STAT1 and c-JUN with STAT3 and is also thought to participate in the negative regulation of these proteins. Distinct genes are bound to STATs via their DBD domain. This domain is also involved in nuclear translocation of activated STAT1 and STAT3 phosphorylated dimers upon cytokine stimulation. LD links the DNA-binding and SH2 domains and is important for the transcriptional activation of STAT1 in response to IFN-gamma. It also plays a role in protein-protein interactions and has also been implicated in the constitutive nucleocytoplasmic shuttling of unphosphorylated STATs in resting cells. The SH2 domain is necessary for receptor association and tyrosine phosphodimer formation. Residues within this domain may be particularly important for some cellular functions mediated by the STATs as well as residues adjacent to this domain. The TAD interacts with several proteins, namely minichromosome maintenance complex component 5 (MCM5), breast cancer 1 (BRCA1) and CBP/p300. TAD also contains a modulatory phosphorylation site that regulates STAT activity and is necessary for maximal transcription of a number of target genes. The conserved tyrosine residue present in the C-terminus is crucial for dimerization via interaction with the SH2 domain upon the interaction of the ligand with the receptor. STAT activation by tyrosine phosphorylation also determines nuclear import and retention, DNA binding to specific DNA elements in the promoters of responsive genes, and transcriptional activation of STAT dimers. In addition to the SH2 domain there is a coiled-coil domain, a DNA binding domain, and a transactivation domain in the STAT proteins. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198235  Cd Length: 151  Bit Score: 318.77  E-value: 2.68e-105
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 557 WIESILELIKKHLLPLWNDGCIMGFISKERERALLKDQQPGTFLLRFSESSREGAITFTWVERSQNGGEPDFHAVEPYTK 636
Cdd:cd10372     1 WIESILELIKKHLLSLWNDGCIMGFISKERERALLKDQQPGTFLLRFSESSREGAITFTWVERSQNGGEPDFHAVEPYTK 80
                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1862756640 637 KELSAVTFPDIIRNYKVMAAENIPENPLKYLYPNIDKDHAFGKYYSRPKEaytmclflAPEPMELDGPKGTGYIKTELI 715
Cdd:cd10372    81 KELSAVTFPDIIRNYKVMAAENIPENPLKYLYPNIDKDHAFGKYYSRPKE--------APEPMELDGPKGTGYIKTELI 151
STAT1_CCD cd16851
Coiled-coil domain of Signal Transducer and Activator of Transcription 1 (STAT1); This family ...
138-313 1.17e-104

Coiled-coil domain of Signal Transducer and Activator of Transcription 1 (STAT1); This family consists of the coiled-coil (alpha) domain of the STAT1 proteins (Signal Transducer and Activator of Transcription 1, or Signal Transduction And Transcription 1). STAT1 plays an essential role in mediating responses to all types of interferons (IFN), transducing signals from cytoplasmic domains of transmembrane receptors into the nucleus where it regulates gene expression. Thus STAT1 is involved in modulating diverse cellular processes, such as antimicrobial activities, cell proliferation and cell death. STAT1 function is crucial in the innate and adaptive arm of immunity and protects from pathogen infections; phosphorylation of a critical tyrosine by Janus kinases (JAKs) leads to its activation and nuclear translocation, while phosphorylation of a critical serine is required for full transcriptional activation upon IFN stimulation and in response to cellular stress. Transcription of protein-encoding genes (including Stat1 itself) as well as expression of microRNAs (miRNAs) is regulated by activated STAT1. Animal studies have shown that STAT1 is generally considered a tumor suppressor but it can also act as a tumor promoter; its functions are not restricted to tumor cells, but extend to parts of the tumor microenvironment such as immune cells, endothelial cells. STAT1 abundance is a reliable marker for good prognosis in selected tumor types, but it can also correlate with disease progression. In head and neck cancer (HNC) patients, upregulation of STAT1-induced HLA class I enhances immunogenicity and clinical response to anti-EGFR mAb cetuximab therapy. In systemic juvenile idiopathic arthritis (sJIA) characterized by systemic inflammation and arthritis, STAT1 phosphorylation downstream of IFNs is impaired. It exerts anti-oncogenic activities through interferon-gamma and interferon-alpha. STAT1 may inhibit hepatocellular carcinoma cell growth by regulating p53-related cell cycling and apoptosis. Studies also show a significant correlation of high STAT1 activity with longer colorectal cancer patient overall survival. Recent studies have shown that STAT1 suppresses mouse mammary gland tumorigenesis by immune regulatory as well as tumor cell-specific functions of STAT1.


Pssm-ID: 341076  Cd Length: 176  Bit Score: 317.88  E-value: 1.17e-104
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 138 KQKELDSKVRNVKDKVMCIEHEIKSLEDLQDEYDFKCKTLQNREHETNGVAKSDQKQEQLLLKKMYLMLDNKRKEVVHKI 217
Cdd:cd16851     1 KQKELDAKVKDLKNSVQDAEQDIKSLEDLQDEYDFKRKTLQSREEETNGVAKEELKKEKLKLRKMFIKLKDKRKEVVHKI 80
                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 218 IELLNVTELTQNALINDELVEWKRRQQSACIGGPPNACLDQLQNWFTIVAESLQQVRQQLKKLEELEQKYTYEHDPITKN 297
Cdd:cd16851    81 IELLNVTELTQFALINDELVEWKRRQQMACIGGPPNACLDQLQNWFTIVAESLQQVRQQLKKLQELEQKLTYENDPITKN 160
                         170
                  ....*....|....*.
gi 1862756640 298 KQVLWDRTFSLFQQLI 313
Cdd:cd16851   161 KQALEERALSLFKNLI 176
STAT_alpha pfam01017
STAT protein, all-alpha domain; STAT proteins (Signal Transducers and Activators of ...
143-309 4.67e-63

STAT protein, all-alpha domain; STAT proteins (Signal Transducers and Activators of Transcription) are a family of transcription factors that are specifically activated to regulate gene transcription when cells encounter cytokines and growth factors. STAT proteins also include an SH2 domain pfam00017.


Pssm-ID: 460026  Cd Length: 167  Bit Score: 208.23  E-value: 4.67e-63
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 143 DSKVRNVKDKVMCIEHEIKSLEDLQDEYDFKCKTLQNREHETNGVAKSDQKQEQLLLKKMYLMLDNKRKEVVHKIIELLN 222
Cdd:pfam01017   1 EQRLEELRNRVQETEQDIKQLEDLQDEFDFKYKTLQKLQQERTESEDKELKQQKELLQQMLNALDQKRKEVLDKLKELLN 80
                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 223 VTELTQNALINDELVEWKRRQQSACIGGPPNACLDQLQNWFTIVAESLQQVRQQLKKLEELEQKYTYEHDPITKNKQVLW 302
Cdd:pfam01017  81 LLETLQELLLDEELIEWKRRQQLACIGAPPNACLDQLQNWFTALAESLWQLRQQLKKLEELRQKLTYEGDPLTDGLPQLN 160

                  ....*..
gi 1862756640 303 DRTFSLF 309
Cdd:pfam01017 161 ERVTELL 167
STAT_int smart00964
STAT protein, protein interaction domain; STAT proteins (Signal Transducers and Activators of ...
2-121 5.78e-58

STAT protein, protein interaction domain; STAT proteins (Signal Transducers and Activators of Transcription) are a family of transcription factors that are specifically activated to regulate gene transcription when cells encounter cytokines and growth factors. STAT proteins also include an SH2 domain.


Pssm-ID: 214942  Cd Length: 120  Bit Score: 192.50  E-value: 5.78e-58
                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640    2 SQWYELQQLDSKFLEQVHQLYDDSFPMEIRQYLAQWLEKQDWEHAANDVSFATIRFHDLLSQLDDQYSRFSLENNFLLQH 81
Cdd:smart00964   1 SQWAQLQQLDSKFLEQVQQLYGDNFPMELRHYLADWIESQDWELAANDEAQATRLFHNLLEQLDQQLSRFSQESNFLLKH 80
                           90       100       110       120
                   ....*....|....*....|....*....|....*....|
gi 1862756640   82 NIRKSKRNLQDNFQEDPIQMSMIIYSCLKEERKILENAQR 121
Cdd:smart00964  81 NLRHIKSNLQSLYQENPLELARIIRNILQEERRILAEASR 120
STAT_bind pfam02864
STAT protein, DNA binding domain; STAT proteins (Signal Transducers and Activators of ...
330-458 1.82e-57

STAT protein, DNA binding domain; STAT proteins (Signal Transducers and Activators of Transcription) are a family of transcription factors that are specifically activated to regulate gene transcription when cells encounter cytokines and growth factors. This family represents the DNA binding domain of STAT, which has an ig-like fold. STAT proteins also include an SH2 domain pfam00017.


Pssm-ID: 460727  Cd Length: 132  Bit Score: 191.64  E-value: 1.82e-57
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 330 QRPLVLKTGVQFTVKLRLLVKLQ---ELNYNLKVKVLFDKDVNERNTVKGFRKFNILG--THTKVMNMEESTNGSLAAEF 404
Cdd:pfam02864   2 QPPQVLKTNTKFSVTVRLLVGLPlniELNPQVKVKIVSEKQARELQQIKGFRKFNISGeiLNNKALLEYESQNGGLSAEF 81
                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1862756640 405 RHLQLKEQKNAGtrtNEGPLIVTEELHSLSFETQLCQPGLVIDLETTSLPVVVI 458
Cdd:pfam02864  82 RNLSLKEIKRGE---RKGSLSVTEEKFALLFETQFTLGGLVFDLWTLSLPVVVI 132
STAT_int pfam02865
STAT protein, protein interaction domain; STAT proteins (Signal Transducers and Activators of ...
2-120 2.86e-56

STAT protein, protein interaction domain; STAT proteins (Signal Transducers and Activators of Transcription) are a family of transcription factors that are specifically activated to regulate gene transcription when cells encounter cytokines and growth factors. STAT proteins also include an SH2 domain pfam00017.


Pssm-ID: 460728  Cd Length: 119  Bit Score: 187.81  E-value: 2.86e-56
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640   2 SQWYELQQLDSKFLEQVHQLYDDSFPMEIRQYLAQWLEKQDWEHAANDVSFATIRFHDLLSQLDDQYSRFSLENNFLLQH 81
Cdd:pfam02865   1 SLWAQLQQLDGEALEQVQQLYGDHFPIEVRHYLAQWIESQDWEDAAQDESLATVLFHALLSELDSQASRFVQEDNFLLKH 80
                          90       100       110
                  ....*....|....*....|....*....|....*....
gi 1862756640  82 NIRKSKRNLQDNFQEDPIQMSMIIYSCLKEERKILENAQ 120
Cdd:pfam02865  81 KLREIAKNLQSRYQENPLELARIIRNCLREERRILQEAE 119
SH2 pfam00017
SH2 domain;
578-622 5.95e-09

SH2 domain;


Pssm-ID: 425423 [Multi-domain]  Cd Length: 77  Bit Score: 53.37  E-value: 5.95e-09
                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 1862756640 578 IMGFISK-ERERALLKDQQPGTFLLRFSESSrEGAITFTWVERSQN 622
Cdd:pfam00017   2 YHGKISRqEAERLLLNGKPDGTFLVRESEST-PGGYTLSVRDDGKV 46
STAT1_TAZ2bind pfam12162
STAT1 TAZ2 binding domain; This domain family is found in eukaryotes, and is approximately 20 ...
723-747 6.15e-05

STAT1 TAZ2 binding domain; This domain family is found in eukaryotes, and is approximately 20 amino acids in length, and the family is found in association with pfam02865, pfam00017, pfam01017, pfam02864. This domain is the C terminal domain of STAT1. This domain binds selectively to the TAZ2 domain of CRB (CREB-binding protein). In this process it becomes a transcriptional activator and can initiate transcription of certain genes.


Pssm-ID: 432372  Cd Length: 23  Bit Score: 40.45  E-value: 6.15e-05
                          10        20
                  ....*....|....*....|....*
gi 1862756640 723 SRLQttDNLLPMSPEEFDEVSRIVG 747
Cdd:pfam12162   1 SRLQ--ENLMPMSPEDYGELERMVR 23
SH2 smart00252
Src homology 2 domains; Src homology 2 domains bind phosphotyrosine-containing polypeptides ...
579-622 3.50e-04

Src homology 2 domains; Src homology 2 domains bind phosphotyrosine-containing polypeptides via 2 surface pockets. Specificity is provided via interaction with residues that are distinct from the phosphotyrosine. Only a single occurrence of a SH2 domain has been found in S. cerevisiae.


Pssm-ID: 214585 [Multi-domain]  Cd Length: 84  Bit Score: 39.90  E-value: 3.50e-04
                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*
gi 1862756640  579 MGFISKERERALLKDQQPGTFLLRFSESSREG-AITFTWVERSQN 622
Cdd:smart00252   5 HGFISREEAEKLLKNEGDGDFLVRDSESSPGDyVLSVRVKGKVKH 49
 
Name Accession Description Interval E-value
STAT1_DBD cd16845
DNA-binding domain of Signal Transducer and Activator of Transcription 1 (STAT1); This family ...
317-477 9.08e-110

DNA-binding domain of Signal Transducer and Activator of Transcription 1 (STAT1); This family consists of the DNA-binding domain (DBD) of the STAT1 proteins (Signal Transducer and Activator of Transcription 1, or Signal Transduction And Transcription 1). The DNA binding domain has an Ig-like fold. STAT1 plays an essential role in mediating responses to all types of interferons (IFN), transducing signals from cytoplasmic domains of transmembrane receptors into the nucleus where it regulates gene expression. Thus STAT1 is involved in modulating diverse cellular processes, such as antimicrobial activities, cell proliferation and cell death. STAT1 function is crucial in the innate and adaptive arm of immunity and protects from pathogen infections; phosphorylation of a critical tyrosine by Janus kinases (JAKs) leads to its activation and nuclear translocation, while phosphorylation of a critical serine is required for full transcriptional activation upon IFN stimulation and in response to cellular stress. Transcription of protein-encoding genes (including Stat1 itself) as well as expression of microRNAs (miRNAs) is regulated by activated STAT1. Animal studies have shown that STAT1 is generally considered a tumor suppressor but it can also act as a tumor promoter; its functions are not restricted to tumor cells, but extend to parts of the tumor microenvironment such as immune cells, endothelial cells. STAT1 abundance is a reliable marker for good prognosis in selected tumor types, but it can also correlate with disease progression. In head and neck cancer (HNC) patients, upregulation of STAT1-induced HLA class I enhances immunogenicity and clinical response to anti-EGFR mAb cetuximab therapy. In systemic juvenile idiopathic arthritis (sJIA) characterized by systemic inflammation and arthritis, STAT1 phosphorylation downstream of IFNs is impaired. It exerts anti-oncogenic activities through interferon-gamma and interferon-alpha. STAT1 may inhibit hepatocellular carcinoma cell growth by regulating p53-related cell cycling and apoptosis. Studies also show a significant correlation of high STAT1 activity with longer colorectal cancer patient overall survival. Recent studies have shown that STAT1 suppresses mouse mammary gland tumorigenesis by immune regulatory as well as tumor cell-specific functions of STAT1.


Pssm-ID: 341083  Cd Length: 161  Bit Score: 330.68  E-value: 9.08e-110
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 317 FVVERQPCMPTHPQRPLVLKTGVQFTVKLRLLVKLQELNYNLKVKVLFDKDVNERNTVKGFRKFNILGTHTKVMNMEEST 396
Cdd:cd16845     1 FVVERQPCMPTHPQRPLVLKTGVQFTVKLRLLVKLQELNYQLKVKVLFDKDVTEKNTVKGFRKFNILGTNTKVMNMEEST 80
                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 397 NGSLAAEFRHLQLKEQKNAGTRTNEGPLIVTEELHSLSFETQLCQPGLVIDLETTSLPVVVISNVSQLPSGWASILWYNM 476
Cdd:cd16845    81 NGSLAAEFRHLQLKEQKNAGTRTNEGPLIVTEELHSLSFETQLCQPGLVIDLETTSLPIVVISNVSQLPSGWASILWYNM 160

                  .
gi 1862756640 477 L 477
Cdd:cd16845   161 L 161
SH2_STAT1 cd10372
Src homology 2 (SH2) domain found in signal transducer and activator of transcription (STAT) 1 ...
557-715 2.68e-105

Src homology 2 (SH2) domain found in signal transducer and activator of transcription (STAT) 1 proteins; STAT1 is a member of the STAT family of transcription factors. STAT1 is involved in upregulating genes due to a signal by interferons. STAT1 forms homodimers or heterodimers with STAT3 that bind to the Interferon-Gamma Activated Sequence (GAS) promoter element in response to IFN-gamma stimulation. STAT1 forms a heterodimer with STAT2 that can bind Interferon Stimulated Response Element (ISRE) promoter element in response to either IFN-alpha or IFN-beta stimulation. Binding in both cases leads to an increased expression of ISG (Interferon Stimulated Genes). STAT1 has been shown to interact with protein kinase R, Src, IRF1, STAT3, MCM5, STAT2, CD117, Fanconi anemia, complementation group C, CREB-binding protein, Interleukin 27 receptor, alpha subunit, PIAS1, BRCA1, Epidermal growth factor receptor, PTK2, Mammalian target of rapamycin, IFNAR2, PRKCD, TRADD, C-jun, Calcitriol receptor, ISGF3G, and GNB2L1. STAT proteins mediate the signaling of cytokines and a number of growth factors from the receptors of these extracellular signaling molecules to the cell nucleus. STATs are specifically phosphorylated by receptor-associated Janus kinases, receptor tyrosine kinases, or cytoplasmic tyrosine kinases. The phosphorylated STAT molecules dimerize by reciprocal binding of their SH2 domains to the phosphotyrosine residues. These dimeric STATs translocate into the nucleus, bind to specific DNA sequences, and regulate the transcription of their target genes. However there are a number of unphosphorylated STATs that travel between the cytoplasm and nucleus and some STATs that exist as dimers in unstimulated cells that can exert biological functions independent of being activated. There are seven mammalian STAT family members which have been identified: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6. There are 6 conserved domains in STAT: N-terminal domain (NTD), coiled-coil domain (CCD), DNA-binding domain (DBD), alpha-helical linker domain (LD), SH2 domain, and transactivation domain (TAD). NTD is involved in dimerization of unphosphorylated STATs monomers and for the tetramerization between STAT1, STAT3, STAT4 and STAT5 on promoters with two or more tandem STAT binding sites. It also plays a role in promoting interactions with transcriptional co-activators such as CREB binding protein (CBP)/p300, as well as being important for nuclear import and deactivation of STATs involving tyrosine de-phosphorylation. CCD interacts with other proteins, such as IFN regulatory protein 9 (IRF-9/p48) with STAT1 and c-JUN with STAT3 and is also thought to participate in the negative regulation of these proteins. Distinct genes are bound to STATs via their DBD domain. This domain is also involved in nuclear translocation of activated STAT1 and STAT3 phosphorylated dimers upon cytokine stimulation. LD links the DNA-binding and SH2 domains and is important for the transcriptional activation of STAT1 in response to IFN-gamma. It also plays a role in protein-protein interactions and has also been implicated in the constitutive nucleocytoplasmic shuttling of unphosphorylated STATs in resting cells. The SH2 domain is necessary for receptor association and tyrosine phosphodimer formation. Residues within this domain may be particularly important for some cellular functions mediated by the STATs as well as residues adjacent to this domain. The TAD interacts with several proteins, namely minichromosome maintenance complex component 5 (MCM5), breast cancer 1 (BRCA1) and CBP/p300. TAD also contains a modulatory phosphorylation site that regulates STAT activity and is necessary for maximal transcription of a number of target genes. The conserved tyrosine residue present in the C-terminus is crucial for dimerization via interaction with the SH2 domain upon the interaction of the ligand with the receptor. STAT activation by tyrosine phosphorylation also determines nuclear import and retention, DNA binding to specific DNA elements in the promoters of responsive genes, and transcriptional activation of STAT dimers. In addition to the SH2 domain there is a coiled-coil domain, a DNA binding domain, and a transactivation domain in the STAT proteins. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198235  Cd Length: 151  Bit Score: 318.77  E-value: 2.68e-105
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 557 WIESILELIKKHLLPLWNDGCIMGFISKERERALLKDQQPGTFLLRFSESSREGAITFTWVERSQNGGEPDFHAVEPYTK 636
Cdd:cd10372     1 WIESILELIKKHLLSLWNDGCIMGFISKERERALLKDQQPGTFLLRFSESSREGAITFTWVERSQNGGEPDFHAVEPYTK 80
                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 1862756640 637 KELSAVTFPDIIRNYKVMAAENIPENPLKYLYPNIDKDHAFGKYYSRPKEaytmclflAPEPMELDGPKGTGYIKTELI 715
Cdd:cd10372    81 KELSAVTFPDIIRNYKVMAAENIPENPLKYLYPNIDKDHAFGKYYSRPKE--------APEPMELDGPKGTGYIKTELI 151
STAT1_CCD cd16851
Coiled-coil domain of Signal Transducer and Activator of Transcription 1 (STAT1); This family ...
138-313 1.17e-104

Coiled-coil domain of Signal Transducer and Activator of Transcription 1 (STAT1); This family consists of the coiled-coil (alpha) domain of the STAT1 proteins (Signal Transducer and Activator of Transcription 1, or Signal Transduction And Transcription 1). STAT1 plays an essential role in mediating responses to all types of interferons (IFN), transducing signals from cytoplasmic domains of transmembrane receptors into the nucleus where it regulates gene expression. Thus STAT1 is involved in modulating diverse cellular processes, such as antimicrobial activities, cell proliferation and cell death. STAT1 function is crucial in the innate and adaptive arm of immunity and protects from pathogen infections; phosphorylation of a critical tyrosine by Janus kinases (JAKs) leads to its activation and nuclear translocation, while phosphorylation of a critical serine is required for full transcriptional activation upon IFN stimulation and in response to cellular stress. Transcription of protein-encoding genes (including Stat1 itself) as well as expression of microRNAs (miRNAs) is regulated by activated STAT1. Animal studies have shown that STAT1 is generally considered a tumor suppressor but it can also act as a tumor promoter; its functions are not restricted to tumor cells, but extend to parts of the tumor microenvironment such as immune cells, endothelial cells. STAT1 abundance is a reliable marker for good prognosis in selected tumor types, but it can also correlate with disease progression. In head and neck cancer (HNC) patients, upregulation of STAT1-induced HLA class I enhances immunogenicity and clinical response to anti-EGFR mAb cetuximab therapy. In systemic juvenile idiopathic arthritis (sJIA) characterized by systemic inflammation and arthritis, STAT1 phosphorylation downstream of IFNs is impaired. It exerts anti-oncogenic activities through interferon-gamma and interferon-alpha. STAT1 may inhibit hepatocellular carcinoma cell growth by regulating p53-related cell cycling and apoptosis. Studies also show a significant correlation of high STAT1 activity with longer colorectal cancer patient overall survival. Recent studies have shown that STAT1 suppresses mouse mammary gland tumorigenesis by immune regulatory as well as tumor cell-specific functions of STAT1.


Pssm-ID: 341076  Cd Length: 176  Bit Score: 317.88  E-value: 1.17e-104
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 138 KQKELDSKVRNVKDKVMCIEHEIKSLEDLQDEYDFKCKTLQNREHETNGVAKSDQKQEQLLLKKMYLMLDNKRKEVVHKI 217
Cdd:cd16851     1 KQKELDAKVKDLKNSVQDAEQDIKSLEDLQDEYDFKRKTLQSREEETNGVAKEELKKEKLKLRKMFIKLKDKRKEVVHKI 80
                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 218 IELLNVTELTQNALINDELVEWKRRQQSACIGGPPNACLDQLQNWFTIVAESLQQVRQQLKKLEELEQKYTYEHDPITKN 297
Cdd:cd16851    81 IELLNVTELTQFALINDELVEWKRRQQMACIGGPPNACLDQLQNWFTIVAESLQQVRQQLKKLQELEQKLTYENDPITKN 160
                         170
                  ....*....|....*.
gi 1862756640 298 KQVLWDRTFSLFQQLI 313
Cdd:cd16851   161 KQALEERALSLFKNLI 176
STAT4_DBD cd16848
DNA-binding domain of Signal Transducer and Activator of Transcription 4 (STAT4); This family ...
317-477 6.04e-81

DNA-binding domain of Signal Transducer and Activator of Transcription 4 (STAT4); This family consists of the DNA-binding domain (DBD) of the STAT4 proteins (Signal Transducer and Activator of Transcription 4, or Signal Transduction And Transcription 4). The DNA binding domain has an Ig-like fold. STAT4 acts as the major signaling transducing STATs in response to interleukin-12 (IL-12) by inducing interferon-gamma (IFNg) , and is a central mediator in generating inflammation during protective immune responses and immune-mediated diseases. STAT4 is a critical regulator of Th1 differentiation and inflammatory disease. It is essential for the differentiation and function of many immune cells, including natural killer cells, dendritic cells, mast cells and T helper cells. STAT4-mediated signaling promotes the production of autoimmune-associated components, which are implicated in the pathogenesis of autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis and psoriasis, making STAT4 a promising therapeutic target for autoimmune diseases. Variations in STAT4 gene are linked to the development of systemic lupus erythematosus (SLE) in humans. STAT4 activation is detected in chronic liver diseases; polymorphism in STAT4 gene has been shown to be associated with the antiviral response in primary biliary cirrhosis (PBC), HCV-associated liver fibrosis, hepatocellular carcinoma (HCC), chronic hepatitis C and in drug-induced liver injury (DILI). STAT4 may inhibit HCC development by modulating HCC cell proliferation. Studies show that increased expression of STAT4 is positively correlated with the depth of invasion in colorectal cancer (CRC) patients, and the growth and invasion of CRC cells are repressed by inhibition of STAT4 expression, making STAT4 a promising therapeutic target for the treatment of CRC.


Pssm-ID: 341086  Cd Length: 152  Bit Score: 255.33  E-value: 6.04e-81
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 317 FVVERQPCMPTHPQRPLVLKTGVQFTVKLRLLVKLQELNYNLKVKVLFDKDvnerntvkgfRKFNILGTHTKVMNMEEST 396
Cdd:cd16848     1 FVVERQPCMPTHPQRPMVLKTLIQFTVKLRLLIKLPELNYQIRVKATIDNN----------RRFVLCGTHVKAMNLEESV 70
                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 397 NGSLAAEFRHLQLKEQK-NAGTRTNEGPLIVTEELHSLSFETQLCQPGLVIDLETTSLPVVVISNVSQLPSGWASILWYN 475
Cdd:cd16848    71 NGSLSVEFRHLQPKEMKpSGGSKGNEGPHMVTEELHSISFETQFSLYGLTIDLETSSLPVVMISNVSQLPNAWASIIWYN 150

                  ..
gi 1862756640 476 ML 477
Cdd:cd16848   151 LL 152
STAT2_DBD cd16846
DNA-binding domain of Signal Transducer and Activator of Transcription 2 (STAT2); This family ...
317-477 1.88e-72

DNA-binding domain of Signal Transducer and Activator of Transcription 2 (STAT2); This family consists of the DNA-binding domain (DBD) of the STAT2 proteins (Signal Transducer and Activator of Transcription 2, or Signal Transduction And Transcription 2). The DNA binding domain has an Ig-like fold. STAT2 activation is driven predominantly by only two classes of cell surface receptors: Type I and III interferon receptors, making it a unique STAT family of transcription factors. Thus, STAT2 plays a critical role in host defenses against viral infections since type I interferon (IFN-I) response inhibits viral replication, and sets the stage for the development of adaptive immunity; viruses target STAT2 by either inhibiting its expression, blocking its activity, or by targeting it for degradation, thus triggering remarkable divergence in the STAT2 gene across species compared to other STAT family members. STAT2 function is regulated by tyrosine phosphorylation which enables STAT dimerization, and subsequent nuclear translocation and transcriptional activation of IFN stimulated genes. Dengue virus (DENV)-mediated degradation of STAT2 has emerged as an important determinant of DENV pathogenesis and host tropism. This vector-borne flavivirus suppresses IFN1 signaling to replicate and cause disease in vertebrates via proteasome-dependent STAT2 degradation mediated by the nonstructural protein NS5 and its interaction partner UBR4, an E3 ubiquitin ligase. The mechanism of Zika virus (ZIKV) NS5 resembles DENV NS5 but through different mechanism - ZIKV does not require the UBR4 to induce STAT2 degradation. It has also been shown that the STAT2 and STAT4 genes are direct targets for transcription factor Oct-1 protein which is involved in the regulation of expression of genes of the JAK-STAT signaling pathway in the Namalwa Burkitt's lymphoma cell line.


Pssm-ID: 341084  Cd Length: 160  Bit Score: 232.79  E-value: 1.88e-72
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 317 FVVERQPCMPTHPQRPLVLKTGVQFTVKLRLLVKLQELNYNLKVKVLFDKDVNernTVKGFRKFNILGTHTKVMNMEEST 396
Cdd:cd16846     1 FVVETQPCMPQPPRRPLVLKTNTQFSVRVRLLVKLPELNHSLKVEVSVDKNPP---NSKGFRRFNILGTNNKTLNMDEGQ 77
                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 397 NGSLAAEFRHLQLKEQK--NAGTRTNEGPLIVTEELHSLSFETQLCQPGLVIDLETTSLPVVVISNVSQLPSGWASILWY 474
Cdd:cd16846    78 SGGLVADFRHLTLKEQKvgGGGKGSNEGSLSVTEELHLITFTTDYKYQGLKVKLETSTLPVVVISNMSQLSSAWASVLWF 157

                  ...
gi 1862756640 475 NML 477
Cdd:cd16846   158 NLL 160
STAT3_DBD cd16847
DNA-binding domain of Signal Transducer and Activator of Transcription 3 (STAT3); This family ...
317-477 3.43e-71

DNA-binding domain of Signal Transducer and Activator of Transcription 3 (STAT3); This family consists of the DNA-binding domain (DBD) of the STAT3 proteins (Signal Transducer and Activator of Transcription 3, or Signal Transduction And Transcription 3). The DNA binding domain has an Ig-like fold. STAT3 plays key roles in vertebrate development and mature tissue function including control of inflammation and immunity. Mutations in human STAT3, especially in the DNA-binding and SH2 domains, are associated with diseases such as autoimmunity, immunodeficiency and cancer. STAT3 regulation is tightly controlled since either inactivation or hyperactivation results in disease. STAT3 activation is stimulated by several cytokines and growth factors, via diverse receptors. For example, IL-6 receptors depend on the tyrosine kinases JAK1 or JAK2, which associate with the cytoplasmic tail of gp130, and results in STAT3 phosphorylation, dimerization, and translocation to the nucleus; this leads to further IL-6 production and up-regulation of anti-apoptotic genes, thus promoting various cellular processes required for cancer progression. Other activators of STAT3 include IL-10, IL-23, and LPS activation of Toll-like receptors TLR4 and TLR9. STAT3 is constitutively activated in numerous cancer types, including over 40% of breast cancers. It has been shown to play a significant role in promoting acute myeloid leukemia (AML) through three mechanisms: promoting proliferation and survival, preventing AML differentiation to functional dendritic cells (DCs), and blocking T-cell function through other pathways. STAT3 also regulates mitochondrion functions, as well as gene expression through epigenetic mechanisms; its activation is induced by overexpression of Bcl-2 via an increase in mitochondrial superoxide. Thus, many of the regulators and functions of JAK-STAT3 in tumors are important therapeutic targets for cancer treatment.


Pssm-ID: 341085  Cd Length: 164  Bit Score: 229.98  E-value: 3.43e-71
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 317 FVVERQPCMPTHPQRPLVLKTGVQFTVKLRLLVKLQELNYNLKVKVLFDKDVNERNTVKGFRKFNILGTHTKVMNMEEST 396
Cdd:cd16847     1 FVVERQPCMPMHPDRPLVIKTGVQFTTKVRLLVKFPELNYQLKIKVCIDKDSGDVAALRGSRKFNILGTNTKVMNMEESN 80
                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 397 NGSLAAEFRHLQLKEQK--NAGTRTNEGPLIVTEELHSLSFETQLCQPGLVIDLETTSLPVVVISNVSQLPSGWASILWY 474
Cdd:cd16847    81 NGSLSAEFKHLTLREQRcgNGGRANCDASLIVTEELHLITFETEVYHQGLKIDLETHSLPVVVISNICQMPNAWASILWY 160

                  ...
gi 1862756640 475 NML 477
Cdd:cd16847   161 NML 163
SH2_STAT4 cd10375
Src homology 2 (SH2) domain found in signal transducer and activator of transcription (STAT) ...
557-682 4.12e-66

Src homology 2 (SH2) domain found in signal transducer and activator of transcription (STAT) 4proteins; STAT4 mediate signals from the IL-12 receptors. STAT4 is mainly phosphorylated by IL-12-mediated signaling pathway in T cells. STAT4 expression is restricted in myeloid cells, thymus and testis. L-12 is the major cytokine that can activate STAT4, resulting in its tyrosine phosphorylation. The IL-12 receptor has two chains, termed IL-12R 1 and IL-12R 2, and ligand binding results in heterodimer formation and activation of the receptor associated JAK kinases, Jak2 and Tyk2. Phosphorylated STAT4 homo-dimerizes via its SH2 domain, and translocates into nucleus where it can recognize traditional N3 STAT target sequences in IL-12 responsive genes. STAT4 can also be phosphorylated in response to IFN-gamma stimulation through activation of Jak1 and Tyk2 in human. IL-17 can also activate STAT4 in human monocytic leukemia cell lines and IL-2 can induce Jak2 and Stat4 activation in NK cells but not in T cells. T helper 1 (Th1) cells produce IL-2 and IFNgamma, whereas Th2 cells secrete IL-4, IL-5, IL-6 and IL-13. Th1 cells are responsible for cell-mediated/inflammatory immunity and can enhance defenses against infectious agents and cancer, while Th2 cells are essential for humoral immunity and the clearance of parasitic antigens. The most potent factors that can promote Th1 and Th2 differentiation are the cytokines IL-12 and IL-4 respectively Although STAT4 is expressed both in Th1 and Th2 cells, STAT4 can only be phosphorylated by IL-12 which suggests that STAT4 plays an important role in Th1 cell function or development. STAT4 activation leads to Th1 differentiation, including the target genes of STAT4 such as ERM, a transcription factor that belongs to the Ets family of transcription factors. The expression of ERM is specifically induced by IL-12 in wild-type Th1 cells, but not in STAT4-deficient T cells. STAT proteins mediate the signaling of cytokines and a number of growth factors from the receptors of these extracellular signaling molecules to the cell nucleus. STATs are specifically phosphorylated by receptor-associated Janus kinases, receptor tyrosine kinases, or cytoplasmic tyrosine kinases. The phosphorylated STAT molecules dimerize by reciprocal binding of their SH2 domains to the phosphotyrosine residues. These dimeric STATs translocate into the nucleus, bind to specific DNA sequences, and regulate the transcription of their target genes. However there are a number of unphosphorylated STATs that travel between the cytoplasm and nucleus and some STATs that exist as dimers in unstimulated cells that can exert biological functions independent of being activated. There are seven mammalian STAT family members which have been identified: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6. There are 6 conserved domains in STAT: N-terminal domain (NTD), coiled-coil domain (CCD), DNA-binding domain (DBD), alpha-helical linker domain (LD), SH2 domain, and transactivation domain (TAD). NTD is involved in dimerization of unphosphorylated STATs monomers and for the tetramerization between STAT1, STAT3, STAT4 and STAT5 on promoters with two or more tandem STAT binding sites. It also plays a role in promoting interactions with transcriptional co-activators such as CREB binding protein (CBP)/p300, as well as being important for nuclear import and deactivation of STATs involving tyrosine de-phosphorylation. CCD interacts with other proteins, such as IFN regulatory protein 9 (IRF-9/p48) with STAT1 and c-JUN with STAT3 and is also thought to participate in the negative regulation of these proteins. Distinct genes are bound to STATs via their DBD domain. This domain is also involved in nuclear translocation of activated STAT1 and STAT3 phosphorylated dimers upon cytokine stimulation. LD links the DNA-binding and SH2 domains and is important for the transcriptional activation of STAT1 in response to IFN-gamma. It also plays a role in protein-protein interactions and has also been implicated in the constitutive nucleocytoplasmic shuttling of unphosphorylated STATs in resting cells. The SH2 domain is necessary for receptor association and tyrosine phosphodimer formation. Residues within this domain may be particularly important for some cellular functions mediated by the STATs as well as residues adjacent to this domain. The TAD interacts with several proteins, namely minichromosome maintenance complex component 5 (MCM5), breast cancer 1 (BRCA1) and CBP/p300. TAD also contains a modulatory phosphorylation site that regulates STAT activity and is necessary for maximal transcription of a number of target genes. The conserved tyrosine residue present in the C-terminus is crucial for dimerization via interaction with the SH2 domain upon the interaction of the ligand with the receptor. STAT activation by tyrosine phosphorylation also determines nuclear import and retention, DNA binding to specific DNA elements in the promoters of responsive genes, and transcriptional activation of STAT dimers. In addition to the SH2 domain there is a coiled-coil domain, a DNA binding domain, and a transactivation domain in the STAT proteins. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198238  Cd Length: 148  Bit Score: 215.52  E-value: 4.12e-66
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 557 WIESILELIKKHLLPLWNDGCIMGFISKERERALLKDQQPGTFLLRFSESSReGAITFTWVERSQNgGEPDFHAVEPYTK 636
Cdd:cd10375     1 WLEAILDLIKKHILPLWIDGYIMGFVSKEKERLLLKDKMPGTFLLRFSESHL-GGITFTWVDQSEN-GEVRFHSVEPYNK 78
                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*.
gi 1862756640 637 KELSAVTFPDIIRNYKVMAAENIPENPLKYLYPNIDKDHAFGKYYS 682
Cdd:cd10375    79 GRLSALPFADILRDYKVIMAENIPENPLKYLYPDIPKDKAFGKHYS 124
STAT_alpha pfam01017
STAT protein, all-alpha domain; STAT proteins (Signal Transducers and Activators of ...
143-309 4.67e-63

STAT protein, all-alpha domain; STAT proteins (Signal Transducers and Activators of Transcription) are a family of transcription factors that are specifically activated to regulate gene transcription when cells encounter cytokines and growth factors. STAT proteins also include an SH2 domain pfam00017.


Pssm-ID: 460026  Cd Length: 167  Bit Score: 208.23  E-value: 4.67e-63
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 143 DSKVRNVKDKVMCIEHEIKSLEDLQDEYDFKCKTLQNREHETNGVAKSDQKQEQLLLKKMYLMLDNKRKEVVHKIIELLN 222
Cdd:pfam01017   1 EQRLEELRNRVQETEQDIKQLEDLQDEFDFKYKTLQKLQQERTESEDKELKQQKELLQQMLNALDQKRKEVLDKLKELLN 80
                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 223 VTELTQNALINDELVEWKRRQQSACIGGPPNACLDQLQNWFTIVAESLQQVRQQLKKLEELEQKYTYEHDPITKNKQVLW 302
Cdd:pfam01017  81 LLETLQELLLDEELIEWKRRQQLACIGAPPNACLDQLQNWFTALAESLWQLRQQLKKLEELRQKLTYEGDPLTDGLPQLN 160

                  ....*..
gi 1862756640 303 DRTFSLF 309
Cdd:pfam01017 161 ERVTELL 167
STAT_DBD cd14801
DNA-binding domain of Signal Transducer and Activator of Transcription (STAT); This family ...
317-477 5.93e-60

DNA-binding domain of Signal Transducer and Activator of Transcription (STAT); This family consists of the DNA binding domain (DBD) of the STAT proteins (Signal Transducer and Activator of Transcription, or Signal Transduction And Transcription), which are latent cytoplasmic transcriptional factors that play an important role in cytokine and growth factor signaling. STAT proteins regulate several aspects of growth, survival and differentiation in cells. The transcription factors of this family are activated by JAK (Janus kinase) and dysregulation of this pathway is frequently observed in primary tumors and leads to immunosuppression, increased angiogenesis and enhanced survival of tumors. There are seven mammalian STAT family members that have been identified: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6. STAT proteins consist of six structural regions: N-terminal domain (ND)/protein interaction domain, coiled-coil domain (CCD)/STAT all alpha domain, DNA-binding domain (DBD), linker domain (LK), a Src homology 2 (SH2) domain, and C-terminal transcriptional activation domain (TA) that includes two conserved phosphorylation sites (tyrosine and serine residues). STAT1 and STAT3 have the greatest diversity of biological functions among the 7 known members of the STAT family. The DNA binding domain of STAT has an Ig-like fold. DNA binding specificity experiments of different STAT proteins show that STAT5A specificity is more similar to that of STAT6 than that of STAT1, as also seen from the evolutionary relationships.


Pssm-ID: 341082  Cd Length: 157  Bit Score: 199.46  E-value: 5.93e-60
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 317 FVVERQPcmpthpqrPLVLKTGVQFTVKLRLLVKLQE--LNYNLKVKVLFDKDVNER-----NTVKGFRKFNILGTHTKV 389
Cdd:cd14801     1 FVVEKQP--------PQVLKTGTKFTATVRLLVGDKLgiHLNLPKVKASIISEEQAKslvenKTLGGFRSGEILGNNTKV 72
                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 390 MNMEESTNGsLAAEFRHLQLKEQKNAGTRtnEGPLIVTEELHSLSFETQLCQPGLVIDLETTSLPVVVISNVSQLPSGWA 469
Cdd:cd14801    73 MEYEESTGG-LSAEFKNLSLKKIKRGDRK--SGDESVTEEKFALLFTTQFTIGGLTIDLWTLSLPVVVIVHGNQEPSAWA 149

                  ....*...
gi 1862756640 470 SILWYNML 477
Cdd:cd14801   150 TILWDNAF 157
SH2_STAT3 cd10374
Src homology 2 (SH2) domain found in signal transducer and activator of transcription (STAT) 3 ...
550-718 8.15e-59

Src homology 2 (SH2) domain found in signal transducer and activator of transcription (STAT) 3 proteins; STAT3 encoded by this gene is a member of the STAT protein family. STAT3 mediates the expression of a variety of genes in response to cell stimuli, and plays a key role in many cellular processes such as cell growth and apoptosis. The small GTPase Rac1 regulates the activity of STAT3 and PIAS3 inhibits it. Three alternatively spliced transcript variants encoding distinct isoforms have been described. STAT 3 activation is required for self-renewal of embryonic stem cells (ESCs) and is essential for the differentiation of the TH17 helper T cells. Mutations in the STAT3 gene result in Hyperimmunoglobulin E syndrome and human cancers. STAT3 has been shown to interact with Androgen receptor, C-jun, ELP2, EP300, Epidermal growth factor receptor, Glucocorticoid receptor, HIF1A, Janus kinase 1, KHDRBS1, Mammalian target of rapamycin, MyoD, NDUFA13, NFKB1, Nuclear receptor coactivator 1, Promyelocytic leukemia protein, RAC1, RELA, RET proto-oncogene, RPA2, Src, STAT1, and TRIP10. STAT proteins mediate the signaling of cytokines and a number of growth factors from the receptors of these extracellular signaling molecules to the cell nucleus. STATs are specifically phosphorylated by receptor-associated Janus kinases, receptor tyrosine kinases, or cytoplasmic tyrosine kinases. The phosphorylated STAT molecules dimerize by reciprocal binding of their SH2 domains to the phosphotyrosine residues. These dimeric STATs translocate into the nucleus, bind to specific DNA sequences, and regulate the transcription of their target genes. However there are a number of unphosphorylated STATs that travel between the cytoplasm and nucleus and some STATs that exist as dimers in unstimulated cells that can exert biological functions independent of being activated. There are seven mammalian STAT family members which have been identified: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6. There are 6 conserved domains in STAT: N-terminal domain (NTD), coiled-coil domain (CCD), DNA-binding domain (DBD), alpha-helical linker domain (LD), SH2 domain, and transactivation domain (TAD). NTD is involved in dimerization of unphosphorylated STATs monomers and for the tetramerization between STAT1, STAT3, STAT4 and STAT5 on promoters with two or more tandem STAT binding sites. It also plays a role in promoting interactions with transcriptional co-activators such as CREB binding protein (CBP)/p300, as well as being important for nuclear import and deactivation of STATs involving tyrosine de-phosphorylation. CCD interacts with other proteins, such as IFN regulatory protein 9 (IRF-9/p48) with STAT1 and c-JUN with STAT3 and is also thought to participate in the negative regulation of these proteins. Distinct genes are bound to STATs via their DBD domain. This domain is also involved in nuclear translocation of activated STAT1 and STAT3 phosphorylated dimers upon cytokine stimulation. LD links the DNA-binding and SH2 domains and is important for the transcriptional activation of STAT1 in response to IFN-gamma. It also plays a role in protein-protein interactions and has also been implicated in the constitutive nucleocytoplasmic shuttling of unphosphorylated STATs in resting cells. The SH2 domain is necessary for receptor association and tyrosine phosphodimer formation. Residues within this domain may be particularly important for some cellular functions mediated by the STATs as well as residues adjacent to this domain. The TAD interacts with several proteins, namely minichromosome maintenance complex component 5 (MCM5), breast cancer 1 (BRCA1) and CBP/p300. TAD also contains a modulatory phosphorylation site that regulates STAT activity and is necessary for maximal transcription of a number of target genes. The conserved tyrosine residue present in the C-terminus is crucial for dimerization via interaction with the SH2 domain upon the interaction of the ligand with the receptor. STAT activation by tyrosine phosphorylation also determines nuclear import and retention, DNA binding to specific DNA elements in the promoters of responsive genes, and transcriptional activation of STAT dimers. In addition to the SH2 domain there is a coiled-coil domain, a DNA binding domain, and a transactivation domain in the STAT proteins. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198237  Cd Length: 162  Bit Score: 196.41  E-value: 8.15e-59
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 550 KNFPFWLWIESILELIKKHLLPLWNDGCIMGFISKERERALLKDQQPGTFLLRFSESSREGAITFTWVERSQNgGEPDFH 629
Cdd:cd10374     4 KGFSFWVWLDNIIDLVKKYILALWNEGYIMGFISKERERAILSTKPPGTFLLRFSESSKEGGVTFTWVEKDIS-GKTQIQ 82
                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 630 AVEPYTKKELSAVTFPDIIRNYKVMAAENIPENPLKYLYPNIDKDHAFGKyYSRPKeaytmclflAPEPMELDGPKGTGY 709
Cdd:cd10374    83 SVEPYTKQQLNNMSFAEIIMGYKIMDATNILVSPLVYLYPDIPKEEAFGK-YCRPE---------SQEHPEADPGSAAPY 152

                  ....*....
gi 1862756640 710 IKTELISVS 718
Cdd:cd10374   153 LKTKFICVT 161
STAT_int smart00964
STAT protein, protein interaction domain; STAT proteins (Signal Transducers and Activators of ...
2-121 5.78e-58

STAT protein, protein interaction domain; STAT proteins (Signal Transducers and Activators of Transcription) are a family of transcription factors that are specifically activated to regulate gene transcription when cells encounter cytokines and growth factors. STAT proteins also include an SH2 domain.


Pssm-ID: 214942  Cd Length: 120  Bit Score: 192.50  E-value: 5.78e-58
                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640    2 SQWYELQQLDSKFLEQVHQLYDDSFPMEIRQYLAQWLEKQDWEHAANDVSFATIRFHDLLSQLDDQYSRFSLENNFLLQH 81
Cdd:smart00964   1 SQWAQLQQLDSKFLEQVQQLYGDNFPMELRHYLADWIESQDWELAANDEAQATRLFHNLLEQLDQQLSRFSQESNFLLKH 80
                           90       100       110       120
                   ....*....|....*....|....*....|....*....|
gi 1862756640   82 NIRKSKRNLQDNFQEDPIQMSMIIYSCLKEERKILENAQR 121
Cdd:smart00964  81 NLRHIKSNLQSLYQENPLELARIIRNILQEERRILAEASR 120
STAT_bind pfam02864
STAT protein, DNA binding domain; STAT proteins (Signal Transducers and Activators of ...
330-458 1.82e-57

STAT protein, DNA binding domain; STAT proteins (Signal Transducers and Activators of Transcription) are a family of transcription factors that are specifically activated to regulate gene transcription when cells encounter cytokines and growth factors. This family represents the DNA binding domain of STAT, which has an ig-like fold. STAT proteins also include an SH2 domain pfam00017.


Pssm-ID: 460727  Cd Length: 132  Bit Score: 191.64  E-value: 1.82e-57
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 330 QRPLVLKTGVQFTVKLRLLVKLQ---ELNYNLKVKVLFDKDVNERNTVKGFRKFNILG--THTKVMNMEESTNGSLAAEF 404
Cdd:pfam02864   2 QPPQVLKTNTKFSVTVRLLVGLPlniELNPQVKVKIVSEKQARELQQIKGFRKFNISGeiLNNKALLEYESQNGGLSAEF 81
                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....
gi 1862756640 405 RHLQLKEQKNAGtrtNEGPLIVTEELHSLSFETQLCQPGLVIDLETTSLPVVVI 458
Cdd:pfam02864  82 RNLSLKEIKRGE---RKGSLSVTEEKFALLFETQFTLGGLVFDLWTLSLPVVVI 132
STAT_int pfam02865
STAT protein, protein interaction domain; STAT proteins (Signal Transducers and Activators of ...
2-120 2.86e-56

STAT protein, protein interaction domain; STAT proteins (Signal Transducers and Activators of Transcription) are a family of transcription factors that are specifically activated to regulate gene transcription when cells encounter cytokines and growth factors. STAT proteins also include an SH2 domain pfam00017.


Pssm-ID: 460728  Cd Length: 119  Bit Score: 187.81  E-value: 2.86e-56
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640   2 SQWYELQQLDSKFLEQVHQLYDDSFPMEIRQYLAQWLEKQDWEHAANDVSFATIRFHDLLSQLDDQYSRFSLENNFLLQH 81
Cdd:pfam02865   1 SLWAQLQQLDGEALEQVQQLYGDHFPIEVRHYLAQWIESQDWEDAAQDESLATVLFHALLSELDSQASRFVQEDNFLLKH 80
                          90       100       110
                  ....*....|....*....|....*....|....*....
gi 1862756640  82 NIRKSKRNLQDNFQEDPIQMSMIIYSCLKEERKILENAQ 120
Cdd:pfam02865  81 KLREIAKNLQSRYQENPLELARIIRNCLREERRILQEAE 119
SH2_STAT_family cd09919
Src homology 2 (SH2) domain found in signal transducer and activator of transcription (STAT) ...
557-682 1.57e-48

Src homology 2 (SH2) domain found in signal transducer and activator of transcription (STAT) family; STAT proteins mediate the signaling of cytokines and a number of growth factors from the receptors of these extracellular signaling molecules to the cell nucleus. STATs are specifically phosphorylated by receptor-associated Janus kinases, receptor tyrosine kinases, or cytoplasmic tyrosine kinases. The phosphorylated STAT molecules dimerize by reciprocal binding of their SH2 domains to the phosphotyrosine residues. These dimeric STATs translocate into the nucleus, bind to specific DNA sequences, and regulate the transcription of their target genes. However there are a number of unphosphorylated STATs that travel between the cytoplasm and nucleus and some STATs that exist as dimers in unstimulated cells that can exert biological functions independent of being activated by a receptor. There are seven mammalian STAT family members which have been identified: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6. There are 6 conserved domains in STAT: N-terminal domain (NTD), coiled-coil domain (CCD), DNA-binding domain (DBD), alpha-helical linker domain (LD), SH2 domain, and transactivation domain (TAD). NTD is involved in dimerization of unphosphorylated STATs monomers and for the tetramerization between STAT1, STAT3, STAT4 and STAT5 on promoters with two or more tandem STAT binding sites. It also plays a role in promoting interactions with transcriptional co-activators such as CREB binding protein (CBP)/p300, as well as being important for nuclear import and deactivation of STATs involving tyrosine de-phosphorylation. The CCD interacts with other proteins, such as IFN regulatory protein 9 (IRF-9/p48) with STAT1 and c-JUN with STAT3 and is also thought to participate in the negative regulation of these proteins. Distinct genes are bound to STATs via their DBD domain. This domain is also involved in nuclear translocation of activated STAT1 and STAT3 phosphorylated dimers upon cytokine stimulation. LD links the DNA-binding and SH2 domains and is important for the transcriptional activation of STAT1 in response to IFN-gamma. It also plays a role in protein-protein interactions and has also been implicated in the constitutive nucleocytoplasmic shuttling of unphosphorylated STATs in resting cells. The SH2 domain is necessary for receptor association and tyrosine phosphodimer formation. Residues within this domain may be particularly important for some cellular functions mediated by the STATs as well as residues adjacent to this domain. The TAD interacts with several proteins, namely minichromosome maintenance complex component 5 (MCM5), breast cancer 1 (BRCA1) and CBP/p300. TAD also contains a modulatory phosphorylation site that regulates STAT activity and is necessary for maximal transcription of a number of target genes. The conserved tyrosine residue present in the C-terminus is crucial for dimerization via interaction with the SH2 domain upon the interaction of the ligand with the receptor. STAT activation by tyrosine phosphorylation also determines nuclear import and retention, DNA binding to specific DNA elements in the promoters of responsive genes, and transcriptional activation of STAT dimers. In addition to the SH2 domain there is a coiled-coil domain, a DNA binding domain, and a transactivation domain in the STAT proteins. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198175  Cd Length: 115  Bit Score: 166.61  E-value: 1.57e-48
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 557 WIESILELIKKHLLPLWNDGCIMGFISKERERALLKDQQPGTFLLRFSESSrEGAITFTWVERSQNgGEPDFHAVEPYTK 636
Cdd:cd09919     1 WFFAIMLLTKRHLLKLWQDGLIMGFISKEEAEDLLKKKPPGTFLLRFSDSE-LGGITIAWVNEDPD-GQSQVIHLQPYTK 78
                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*.
gi 1862756640 637 KELSAVTFPDIIRNYKvmaaenipenPLKYLYPNIDKDHAFGKYYS 682
Cdd:cd09919    79 KDLDIRSLADRIRDLP----------QLVYLYPDIPKDEAFGKYYS 114
SH2_STAT2 cd10373
Src homology 2 (SH2) domain found in signal transducer and activator of transcription (STAT) 2 ...
557-681 3.63e-45

Src homology 2 (SH2) domain found in signal transducer and activator of transcription (STAT) 2 proteins; STAT2 is a member of the STAT protein family. In response to interferon, STAT2 forms a complex with STAT1 and IFN regulatory factor family protein p48 (ISGF3G), in which this protein acts as a transactivator, but lacks the ability to bind DNA directly. Transcription adaptor P300/CBP (EP300/CREBBP) has been shown to interact specifically with STAT2, which is thought to be involved in the process of blocking IFN-alpha response by adenovirus. STAT2 has been shown to interact with MED14, CREB-binding protein, SMARCA4, STAT1, IFNAR2, IFNAR1, and ISGF3G. STAT proteins mediate the signaling of cytokines and a number of growth factors from the receptors of these extracellular signaling molecules to the cell nucleus. STATs are specifically phosphorylated by receptor-associated Janus kinases, receptor tyrosine kinases, or cytoplasmic tyrosine kinases. The phosphorylated STAT molecules dimerize by reciprocal binding of their SH2 domains to the phosphotyrosine residues. These dimeric STATs translocate into the nucleus, bind to specific DNA sequences, and regulate the transcription of their target genes. However there are a number of unphosphorylated STATs that travel between the cytoplasm and nucleus and some STATs that exist as dimers in unstimulated cells that can exert biological functions independent of being activated. There are seven mammalian STAT family members which have been identified: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6. There are 6 conserved domains in STAT: N-terminal domain (NTD), coiled-coil domain (CCD), DNA-binding domain (DBD), alpha-helical linker domain (LD), SH2 domain, and transactivation domain (TAD). NTD is involved in dimerization of unphosphorylated STATs monomers and for the tetramerization between STAT1, STAT3, STAT4 and STAT5 on promoters with two or more tandem STAT binding sites. It also plays a role in promoting interactions with transcriptional co-activators such as CREB binding protein (CBP)/p300, as well as being important for nuclear import and deactivation of STATs involving tyrosine de-phosphorylation. CCD interacts with other proteins, such as IFN regulatory protein 9 (IRF-9/p48) with STAT1 and c-JUN with STAT3 and is also thought to participate in the negative regulation of these proteins. Distinct genes are bound to STATs via their DBD domain. This domain is also involved in nuclear translocation of activated STAT1 and STAT3 phosphorylated dimers upon cytokine stimulation. LD links the DNA-binding and SH2 domains and is important for the transcriptional activation of STAT1 in response to IFN-gamma. It also plays a role in protein-protein interactions and has also been implicated in the constitutive nucleocytoplasmic shuttling of unphosphorylated STATs in resting cells. The SH2 domain is necessary for receptor association and tyrosine phosphodimer formation. Residues within this domain may be particularly important for some cellular functions mediated by the STATs as well as residues adjacent to this domain. The TAD interacts with several proteins, namely minichromosome maintenance complex component 5 (MCM5), breast cancer 1 (BRCA1) and CBP/p300. TAD also contains a modulatory phosphorylation site that regulates STAT activity and is necessary for maximal transcription of a number of target genes. The conserved tyrosine residue present in the C-terminus is crucial for dimerization via interaction with the SH2 domain upon the interaction of the ligand with the receptor. STAT activation by tyrosine phosphorylation also determines nuclear import and retention, DNA binding to specific DNA elements in the promoters of responsive genes, and transcriptional activation of STAT dimers. In addition to the SH2 domain there is a coiled-coil domain, a DNA binding domain, and a transactivation domain in the STAT proteins. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198236  Cd Length: 151  Bit Score: 158.90  E-value: 3.63e-45
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 557 WIESILELIKKHLLPLWNDGCIMGFISKERERALLKDQQPGTFLLRFSESSrEGAITFTWVERsQNGGEPDFHAVEPYTK 636
Cdd:cd10373     1 WLDKILELVHDHLKDLWKDGRIMGFVSRNQERRLLKKTISGTFLLRFSETS-EGGITCSWVEH-QDDDKVLIYSVQPYTK 78
                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 1862756640 637 KELSAVTFPDIIRNYKVMAAENIPENPLKYLYPNIDKDHAFGKYY 681
Cdd:cd10373    79 EVLQSLPLTEIIRHYQLLTEENIPENPLRFLYPRIPRDEAFGCYY 123
STAT3_CCD cd16853
Coiled-coil domain of Signal Transducer and Activator of Transcription 3 (STAT3); This family ...
137-314 2.71e-43

Coiled-coil domain of Signal Transducer and Activator of Transcription 3 (STAT3); This family consists of the coiled-coil (alpha) domain of the STAT3 proteins (Signal Transducer and Activator of Transcription 3, or Signal Transduction And Transcription 3). STAT3 continuously shuttles between nuclear and cytoplasmic compartments. The coiled-coil domain (CCD) of STAT3 appears to be required for constitutive nuclear localization signals (NLS) function; small deletions within the STAT3 CCD can abrogate nuclear import. Studies show that the CCD binds to the importin-alpha3 in the testis, and importin-alpha6 NLS adapters in most cells. STAT3 plays key roles in vertebrate development and mature tissue function including control of inflammation and immunity. Mutations in human STAT3, especially in the DNA-binding and SH2 domains, are associated with diseases such as autoimmunity, immunodeficiency and cancer. STAT3 regulation is tightly controlled since either inactivation or hyperactivation results in disease. STAT3 activation is stimulated by several cytokines and growth factors, via diverse receptors. For example, IL-6 receptors depend on the tyrosine kinases JAK1 or JAK2, which associate with the cytoplasmic tail of gp130, and results in STAT3 phosphorylation, dimerization, and translocation to the nucleus; this leads to further IL-6 production and up-regulation of anti-apoptotic genes, thus promoting various cellular processes required for cancer progression. Other activators of STAT3 include IL-10, IL-23, and LPS activation of Toll-like receptors TLR4 and TLR9. STAT3 is constitutively activated in numerous cancer types, including over 40% of breast cancers. It has been shown to play a significant role in promoting acute myeloid leukemia (AML) through three mechanisms: promoting proliferation and survival, preventing AML differentiation to functional dendritic cells (DCs), and blocking T-cell function through other pathways. STAT3 also regulates mitochondrion functions, as well as gene expression through epigenetic mechanisms; its activation is induced by overexpression of Bcl-2 via an increase in mitochondrial superoxide. Thus, many of the regulators and functions of JAK-STAT3 in tumors are important therapeutic targets for cancer treatment.


Pssm-ID: 341078 [Multi-domain]  Cd Length: 180  Bit Score: 154.77  E-value: 2.71e-43
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 137 DKQKELDSKVRNVKDKVMCIEHEIKSLEDLQDEYDFKCKTL--QNREHETNGVAKSDQKQEQLLLKKMYLMLDNKRKEVV 214
Cdd:cd16853     1 EKQQMLEQHLQDVRKRVQDLEQKMKVVENLQDDFDFNYKTLksQGDMQDLNGNNQSVTRQKMQQLEQMLTALDQMRRQIV 80
                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 215 HKIIELLNVTELTQNALINDELVEWKRRQQSACIGGPPNACLDQLQNWFTIVAESLQQVRQQLKKLEELEQKYTYEHDPI 294
Cdd:cd16853    81 SELAGLLSAMEYVQKNLTDEELADWKRRQQIACIGGPPNICLDRLENWITSLAESQLQTRQQIKKLEELQQKVSYKGDPI 160
                         170       180
                  ....*....|....*....|
gi 1862756640 295 TKNKQVLWDRTFSLFQQLIQ 314
Cdd:cd16853   161 VQHRPMLEERIVELFRNLMK 180
STAT4_CCD cd16854
Coiled-coil domain of Signal Transducer and Activator of Transcription 4 (STAT4); This family ...
139-313 5.35e-41

Coiled-coil domain of Signal Transducer and Activator of Transcription 4 (STAT4); This family consists of the coiled-coil (alpha) domain of the STAT4 proteins (Signal Transducer and Activator of Transcription 4, or Signal Transduction And Transcription 4). STAT4 expression is restricted to spermatozoa, myeloid cells, and T lymphocytes, making it distinct from other STATs. It acts as the major signaling transducing STATs in response to interleukin-12 (IL-12) by inducing interferon-gamma (IFNgamma), and is a central mediator in generating inflammation during protective immune responses and immune-mediated diseases. STAT4 is a critical regulator of Th1 differentiation and inflammatory disease. It is essential for the differentiation and function of many immune cells, including natural killer cells, dendritic cells, mast cells and T helper cells. STAT4-mediated signaling promotes the production of autoimmune-associated components, which are implicated in the pathogenesis of autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis and psoriasis, making STAT4 a promising therapeutic target for autoimmune diseases. Variations in STAT4 gene are linked to the development of systemic lupus erythematosus (SLE) in humans. STAT4 activation is detected in chronic liver diseases; polymorphism in STAT4 gene has been shown to be associated with the antiviral response in primary biliary cirrhosis (PBC), HCV-associated liver fibrosis, hepatocellular carcinoma (HCC), chronic hepatitis C and in drug-induced liver injury (DILI). STAT4 may inhibit HCC development by modulating HCC cell proliferation. Studies show that increased expression of STAT4 is positively correlated with the depth of invasion in colorectal cancer (CRC) patients, and the growth and invasion of CRC cells are repressed by inhibition of STAT4 expression, making STAT4 a promising therapeutic target for the treatment of CRC.


Pssm-ID: 341079  Cd Length: 173  Bit Score: 147.70  E-value: 5.35e-41
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 139 QKELDSKVRNVKDKVMCIEHEIKSLEDLQDEYDFKCKTLQNRE-HETNgvaKSDQKQEQLLLKKMYLMLDNKRKEVVHKI 217
Cdd:cd16854     1 QRNVEHKVSAIKNSVQMTDQDTKYLEDLQDEFDFRYKTIQTMDqGDKN---SILMKQEVTTLQEMLNSLDFKRKEALSKM 77
                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 218 IELLNVTELTQNALINDELVEWKRRQQSACIGGPPNACLDQLQNWFTIVAESLQQVRQQLKKLEELEQKYTYEHDPITKN 297
Cdd:cd16854    78 TQIINEIDLLMSSMLTEELKDWKRRQQIACIGGPLHGGLDQLQNWFTLLAESLFQLRRQLEKLDELSTKVTYEGDPIPLQ 157
                         170
                  ....*....|....*.
gi 1862756640 298 KQVLWDRTFSLFQQLI 313
Cdd:cd16854   158 RPQLLERVTFLIYNLF 173
STAT2_CCD cd16852
Coiled-coil domain of Signal Transducer and Activator of Transcription 2 (STAT2); This family ...
139-313 2.75e-40

Coiled-coil domain of Signal Transducer and Activator of Transcription 2 (STAT2); This family consists of the coiled-coil (alpha) domain of the STAT2 proteins (Signal Transducer and Activator of Transcription 2, or Signal Transduction And Transcription 2). STAT2 activation is driven predominantly by only two classes of cell surface receptors: Type I and III interferon receptors, making it a unique STAT family of transcription factors. It differs from other STAT family members in that it associates constitutively with a non-STAT protein, the interferon regulatory factor 9 (IRF9). The coiled-coil domain of STAT2 is necessary for binding the carboxyl terminus of IRF9, an association required for the constitutive nuclear import of unphosphorylated STAT2. STAT2 plays a critical role in host defenses against viral infections since type I interferon (IFN-I) response inhibits viral replication, and sets the stage for the development of adaptive immunity; viruses target STAT2 by either inhibiting its expression, blocking its activity, or by targeting it for degradation, thus triggering remarkable divergence in the STAT2 gene across species compared to other STAT family members. STAT2 function is regulated by tyrosine phosphorylation which enables STAT dimerization, and subsequent nuclear translocation and transcriptional activation of IFN stimulated genes. Dengue virus (DENV)-mediated degradation of STAT2 has emerged as an important determinant of DENV pathogenesis and host tropism. This vector-borne flavivirus suppresses IFN1 signaling to replicate and cause disease in vertebrates via proteasome-dependent STAT2 degradation mediated by the nonstructural protein NS5 and its interaction partner UBR4, an E3 ubiquitin ligase. The mechanism of Zika virus (ZIKV) NS5 resembles DENV NS5 but through different mechanism - ZIKV does not require the UBR4 to induce STAT2 degradation. It has also been shown that the STAT2 and STAT4 genes are direct targets for transcription factor Oct-1 protein which is involved in the regulation of expression of genes of the JAK-STAT signaling pathway in the Namalwa Burkitt's lymphoma cell line.


Pssm-ID: 341077  Cd Length: 172  Bit Score: 146.00  E-value: 2.75e-40
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 139 QKELDSKVRNVKDKVMCIEHEIKSLEDLQDEYDFKCKTLQnrEHETNGVAKSDQKQEQLLLKKMYLMlDNKRKEVVHKII 218
Cdd:cd16852     2 QHEIEKRINDLKTRIQCLEHSIRQLEDLQDTFDFKYKTHT--MDKSTSPDDKQTKQQQILQGMLNEL-DRFRKEVLSKMK 78
                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 219 ELLNVTELTQNaLINDELVEWKRRQQSACIGGPPNACLDQLQNWFTIVAESLQQVRQQLKKLEELEQKYTYEHDPITKNK 298
Cdd:cd16852    79 VLLGRRDTLRE-LLLEELVEWKRRQQKACIGAPDDTSLEQLEKWFTKVAECLFQLRKFLKKLEELMGKVSYEHDPLKKQK 157
                         170
                  ....*....|....*
gi 1862756640 299 QVLWDRTFSLFQQLI 313
Cdd:cd16852   158 PLLQQRVDELLTSLL 172
STAT_CCD cd14786
Coiled-coil domain of Signal Transducer and Activator of Transcription (STAT), also called ...
141-313 1.54e-32

Coiled-coil domain of Signal Transducer and Activator of Transcription (STAT), also called alpha domain; This family consists of the coiled-coil (alpha) domain of the STAT proteins (Signal Transducer and Activator of Transcription, or Signal Transduction And Transcription), which are latent cytoplasmic transcriptional factors that play an important role in cytokine and growth factor signaling. STAT proteins regulate several aspects of growth, survival and differentiation in cells. The transcription factors of this family are activated by JAK (Janus kinase) and dysregulation of this pathway is frequently observed in primary tumors and leads to immunosuppression, increased angiogenesis and enhanced survival of tumors. There are seven mammalian STAT family members that have been identified: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B and STAT6. STAT proteins consist of six structural regions: N-domain (ND)/protein interaction domain, coiled-coil domain (CCD)/STAT all alpha domain, DNA-binding domain (DBD), linker domain (LK), a Src homology 2 (SH2) domain, and C-terminal transcriptional activation domain (TA) that includes two conserved phosphorylation sites (tyrosine and serine residues). The coiled-coil or alpha domain is an interacting region with other proteins, including IRF-9/p48 for STAT1, c-Jun, StIP1, and GRIM-19 for STAT3, and SMRT with STAT5A and STAT5B. A functional STAT1 mutant (phenylalanine to serine) in this domain region shows significantly decreased protein expression caused by translational/post-translational mechanisms independent of proteasome machinery. The phenylalanine is not conserved in STAT4 and STAT6 that have tight specificity, suggesting a novel potential mechanism of specific activation of STAT proteins. Specifically, STAT3, STAT5, and STAT6, which are continually imported to the nucleus independent of tyrosine phosphorylation, require the conformational structure of their coiled-coil domains.


Pssm-ID: 341075  Cd Length: 125  Bit Score: 122.02  E-value: 1.54e-32
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 141 ELDSKVRNVKDKVMCIEHEIKSLEDlqdeydfkcktlqnrehetngvaksdqkqeqlllkkmylmldnKRKEVVHKIIEL 220
Cdd:cd14786     2 ELEQQILQLRNEFQILWEELKSLQQ-------------------------------------------KRKEVLVKLLRR 38
                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 221 LNVTELTQNALINDELVEWKRRQQSACIGGPPNACLDQLQNWFTIVAESLQQVRQQLKKLEELeqkytyEHDPITKNKQV 300
Cdd:cd14786    39 LLMAEEIQQELIIEELKNWKRRQQLAGNGAPREQSLDELQNWFESLAEFLWQLRQQVKKLLEL------FGDPIDPQLND 112
                         170
                  ....*....|...
gi 1862756640 301 LWDRTFSLFQQLI 313
Cdd:cd14786   113 LLERVQELQKNLV 125
SH2_STAT6 cd10377
Src homology 2 (SH2) domain found in signal transducer and activator of transcription (STAT) 6 ...
557-684 7.97e-30

Src homology 2 (SH2) domain found in signal transducer and activator of transcription (STAT) 6 proteins; STAT6 mediate signals from the IL-4 receptor. Unlike the other STAT proteins which bind an IFNgamma Activating Sequence (GAS), STAT6 stands out as having a unique binding site preference. This site consists of a palindromic sequence separated by a 3 bp spacer (TTCNNNG-AA)(N3 site). STAT6 is able to bind the GAS site but only at a low affinity. STAT6 may be an important regulator of mitogenesis when cells respond normally to IL-4. There is speculation that the inappropriate activation of STAT6 is involved in uncontrolled cell growth in an oncogenic state. IFNgamma is a negative regulator of STAT6 dependent transcription of target genes. Bcl-6 is another negative regulator of STAT6 activity. Bcl-6 is a transcriptional repressor normally expressed in germinal center B cells and some T cells. IL-4 signaling via STAT6 initially occurs unopposed, but is then dampened by a negative feedback mechanism through the IL-4/Stat6 dependent induction of SOCS1 expression. The IL-4 dependent aspect of Th2 differentiation requires the activation of STAT6. IL-4 signaling and STAT6 appear to play an important role in the immune response. Recently, it was shown that large scale chromatin remodeling of the IL-4 gene occurs as cells differentiate into Th2 effectors is STAT6 dependent. STAT proteins mediate the signaling of cytokines and a number of growth factors from the receptors of these extracellular signaling molecules to the cell nucleus. STATs are specifically phosphorylated by receptor-associated Janus kinases, receptor tyrosine kinases, or cytoplasmic tyrosine kinases. The phosphorylated STAT molecules dimerize by reciprocal binding of their SH2 domains to the phosphotyrosine residues. These dimeric STATs translocate into the nucleus, bind to specific DNA sequences, and regulate the transcription of their target genes. However there are a number of unphosphorylated STATs that travel between the cytoplasm and nucleus and some STATs that exist as dimers in unstimulated cells that can exert biological functions independent of being activated. There are seven mammalian STAT family members which have been identified: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6. There are 6 conserved domains in STAT: N-terminal domain (NTD), coiled-coil domain (CCD), DNA-binding domain (DBD), alpha-helical linker domain (LD), SH2 domain, and transactivation domain (TAD). NTD is involved in dimerization of unphosphorylated STATs monomers and for the tetramerization between STAT1, STAT3, STAT4 and STAT5 on promoters with two or more tandem STAT binding sites. It also plays a role in promoting interactions with transcriptional co-activators such as CREB binding protein (CBP)/p300, as well as being important for nuclear import and deactivation of STATs involving tyrosine de-phosphorylation. CCD interacts with other proteins, such as IFN regulatory protein 9 (IRF-9/p48) with STAT1 and c-JUN with STAT3 and is also thought to participate in the negative regulation of these proteins. Distinct genes are bound to STATs via their DBD domain. This domain is also involved in nuclear translocation of activated STAT1 and STAT3 phosphorylated dimers upon cytokine stimulation. LD links the DNA-binding and SH2 domains and is important for the transcriptional activation of STAT1 in response to IFN-gamma. It also plays a role in protein-protein interactions and has also been implicated in the constitutive nucleocytoplasmic shuttling of unphosphorylated STATs in resting cells. The SH2 domain is necessary for receptor association and tyrosine phosphodimer formation. Residues within this domain may be particularly important for some cellular functions mediated by the STATs as well as residues adjacent to this domain. The TAD interacts with several proteins, namely minichromosome maintenance complex component 5 (MCM5), breast cancer 1 (BRCA1) and CBP/p300. TAD also contains a modulatory phosphorylation site that regulates STAT activity and is necessary for maximal transcription of a number of target genes. The conserved tyrosine residue present in the C-terminus is crucial for dimerization via interaction with the SH2 domain upon the interaction of the ligand with the receptor. STAT activation by tyrosine phosphorylation also determines nuclear import and retention, DNA binding to specific DNA elements in the promoters of responsive genes, and transcriptional activation of STAT dimers. In addition to the SH2 domain there is a coiled-coil domain, a DNA binding domain, and a transactivation domain in the STAT proteins. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198240  Cd Length: 129  Bit Score: 114.50  E-value: 7.97e-30
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 557 WIESILELIKKHLLPLWNDGCIMGFISKERERALLKDQQPGTFLLRFSESSReGAITFTWVERSQNGGEpDFHAVEPYTK 636
Cdd:cd10377     1 WFDGVLDLTKRCLRSYWSDRLIIGFISKQYVTSLLLNEPDGTFLLRFSDSEI-GGITIAHVIRGQDGSP-QIENIQPFSA 78
                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*...
gi 1862756640 637 KELSAVTFPDIIRNYKvmaaenipenPLKYLYPNIDKDHAFGKYYSRP 684
Cdd:cd10377    79 KDLSIRSLGDRIRDLA----------QLKNLYPKKPKDEAFRSHYKPE 116
SH2_STAT5 cd10376
Src homology 2 (SH2) domain found in signal transducer and activator of transcription (STAT) 5 ...
557-717 4.19e-20

Src homology 2 (SH2) domain found in signal transducer and activator of transcription (STAT) 5 proteins; STAT5 is a member of the STAT family of transcription factors. Two highly related proteins, STAT5a and STAT5b are encoded by separate genes, but are 90% identical at the amino acid level. Both STAT5a and STAT5b are ubiquitously expressed and functionally interchangeable. Mice lacking either STAT5a or STAT5b have mild defects in prolactin dependent mammary differentiation or sexually dimorphic growth hormone-dependent effects, respectively. Mice lacking both STAT5a and STAT5b exhibit a perinatal lethal phenotype and have multiple defects, including anemia and a virtual absence of B and T lymphocytes. STAT proteins mediate the signaling of cytokines and a number of growth factors from the receptors of these extracellular signaling molecules to the cell nucleus. STATs are specifically phosphorylated by receptor-associated Janus kinases, receptor tyrosine kinases, or cytoplasmic tyrosine kinases. The phosphorylated STAT molecules dimerize by reciprocal binding of their SH2 domains to the phosphotyrosine residues. These dimeric STATs translocate into the nucleus, bind to specific DNA sequences, and regulate the transcription of their target genes. However there are a number of unphosphorylated STATs that travel between the cytoplasm and nucleus and some STATs that exist as dimers in unstimulated cells that can exert biological functions independent of being activated. There are seven mammalian STAT family members which have been identified: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6. There are 6 conserved domains in STAT: N-terminal domain (NTD), coiled-coil domain (CCD), DNA-binding domain (DBD), alpha-helical linker domain (LD), SH2 domain, and transactivation domain (TAD). NTD is involved in dimerization of unphosphorylated STATs monomers and for the tetramerization between STAT1, STAT3, STAT4 and STAT5 on promoters with two or more tandem STAT binding sites. It also plays a role in promoting interactions with transcriptional co-activators such as CREB binding protein (CBP)/p300, as well as being important for nuclear import and deactivation of STATs involving tyrosine de-phosphorylation. CCD interacts with other proteins, such as IFN regulatory protein 9 (IRF-9/p48) with STAT1 and c-JUN with STAT3 and is also thought to participate in the negative regulation of these proteins. Distinct genes are bound to STATs via their DBD domain. This domain is also involved in nuclear translocation of activated STAT1 and STAT3 phosphorylated dimers upon cytokine stimulation. LD links the DNA-binding and SH2 domains and is important for the transcriptional activation of STAT1 in response to IFN-gamma. It also plays a role in protein-protein interactions and has also been implicated in the constitutive nucleocytoplasmic shuttling of unphosphorylated STATs in resting cells. The SH2 domain is necessary for receptor association and tyrosine phosphodimer formation. Residues within this domain may be particularly important for some cellular functions mediated by the STATs as well as residues adjacent to this domain. The TAD interacts with several proteins, namely minichromosome maintenance complex component 5 (MCM5), breast cancer 1 (BRCA1) and CBP/p300. TAD also contains a modulatory phosphorylation site that regulates STAT activity and is necessary for maximal transcription of a number of target genes. The conserved tyrosine residue present in the C-terminus is crucial for dimerization via interaction with the SH2 domain upon the interaction of the ligand with the receptor. STAT activation by tyrosine phosphorylation also determines nuclear import and retention, DNA binding to specific DNA elements in the promoters of responsive genes, and transcriptional activation of STAT dimers. In addition to the SH2 domain there is a coiled-coil domain, a DNA binding domain, and a transactivation domain in the STAT proteins.


Pssm-ID: 198239  Cd Length: 137  Bit Score: 86.95  E-value: 4.19e-20
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 557 WIESILELIKKHLLPLWNDGCIMGFISKERERALLKDQQPGTFLLRFSESSReGAITFTWVERSQnggEPDFHAVEPYTK 636
Cdd:cd10376     1 WFDGVMEVLKKHLKPHWNDGAILGFVNKQQAHDLLINKPDGTFLLRFSDSEI-GGITIAWKFDSP---DRALWNLMPFTT 76
                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 637 KELSAVTFPDIIRNYkvmaaenipeNPLKYLYPNIDKDHAFGKYYSrpkeaytmclflapePMELDGPKGTGYIKTELIS 716
Cdd:cd10376    77 RDFSIRSLADRLGDL----------NYLIYVFPDRPKDEVFSKYYT---------------PVLCNPSAVDGYVKPQIKQ 131

                  .
gi 1862756640 717 V 717
Cdd:cd10376   132 V 132
SH2_STAT5b cd10420
Src homology 2 (SH2) domain found in signal transducer and activator of transcription (STAT) ...
557-717 7.14e-20

Src homology 2 (SH2) domain found in signal transducer and activator of transcription (STAT) 5b proteins; STAT5 is a member of the STAT family of transcription factors. Two highly related proteins, STAT5a and STAT5b are encoded by separate genes, but are 90% identical at the amino acid level. Both STAT5a and STAT5b are ubiquitously expressed and functionally interchangeable. Mice lacking either STAT5a or STAT5b have mild defects in prolactin dependent mammary differentiation or sexually dimorphic growth hormone-dependent effects, respectively. Mice lacking both STAT5a and STAT5b exhibit a perinatal lethal phenotype and have multiple defects, including anemia and a virtual absence of B and T lymphocytes. STAT proteins mediate the signaling of cytokines and a number of growth factors from the receptors of these extracellular signaling molecules to the cell nucleus. STATs are specifically phosphorylated by receptor-associated Janus kinases, receptor tyrosine kinases, or cytoplasmic tyrosine kinases. The phosphorylated STAT molecules dimerize by reciprocal binding of their SH2 domains to the phosphotyrosine residues. These dimeric STATs translocate into the nucleus, bind to specific DNA sequences, and regulate the transcription of their target genes. However there are a number of unphosphorylated STATs that travel between the cytoplasm and nucleus and some STATs that exist as dimers in unstimulated cells that can exert biological functions independent of being activated. There are seven mammalian STAT family members which have been identified: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6. There are 6 conserved domains in STAT: N-terminal domain (NTD), coiled-coil domain (CCD), DNA-binding domain (DBD), alpha-helical linker domain (LD), SH2 domain, and transactivation domain (TAD). NTD is involved in dimerization of unphosphorylated STATs monomers and for the tetramerization between STAT1, STAT3, STAT4 and STAT5 on promoters with two or more tandem STAT binding sites. It also plays a role in promoting interactions with transcriptional co-activators such as CREB binding protein (CBP)/p300, as well as being important for nuclear import and deactivation of STATs involving tyrosine de-phosphorylation. CCD interacts with other proteins, such as IFN regulatory protein 9 (IRF-9/p48) with STAT1 and c-JUN with STAT3 and is also thought to participate in the negative regulation of these proteins. Distinct genes are bound to STATs via their DBD domain. This domain is also involved in nuclear translocation of activated STAT1 and STAT3 phosphorylated dimers upon cytokine stimulation. LD links the DNA-binding and SH2 domains and is important for the transcriptional activation of STAT1 in response to IFN-gamma. It also plays a role in protein-protein interactions and has also been implicated in the constitutive nucleocytoplasmic shuttling of unphosphorylated STATs in resting cells. The SH2 domain is necessary for receptor association and tyrosine phosphodimer formation. Residues within this domain may be particularly important for some cellular functions mediated by the STATs as well as residues adjacent to this domain. The TAD interacts with several proteins, namely minichromosome maintenance complex component 5 (MCM5), breast cancer 1 (BRCA1) and CBP/p300. TAD also contains a modulatory phosphorylation site that regulates STAT activity and is necessary for maximal transcription of a number of target genes. The conserved tyrosine residue present in the C-terminus is crucial for dimerization via interaction with the SH2 domain upon the interaction of the ligand with the receptor. STAT activation by tyrosine phosphorylation also determines nuclear import and retention, DNA binding to specific DNA elements in the promoters of responsive genes, and transcriptional activation of STAT dimers. In addition to the SH2 domain there is a coiled-coil domain, a DNA binding domain, and a transactivation domain in the STAT proteins. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198283  Cd Length: 145  Bit Score: 86.67  E-value: 7.14e-20
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 557 WIESILELIKKHLLPLWNDGCIMGFISKERERALLKDQQPGTFLLRFSESSReGAITFTWVERSQnggEPDFHAVEPYTK 636
Cdd:cd10420     1 WFDGVMEVLKKHLKPHWNDGAILGFVNKQQAHDLLINKPDGTFLLRFSDSEI-GGITIAWKFDSQ---ERMFWNLMPFTT 76
                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 637 KELSAVTFPDIIRNYKVmaaenipenpLKYLYPNIDKDHAFGKYYSrpkeaytmclflaPEPMELDGPKGT-GYIKTELI 715
Cdd:cd10420    77 RDFSIRSLADRLGDLNY----------LIYVFPDRPKDEVYSKYYT-------------PVPCEPATAKAVdGYVKPQIK 133

                  ..
gi 1862756640 716 SV 717
Cdd:cd10420   134 QV 135
SH2_STAT5a cd10421
Src homology 2 (SH2) domain found in signal transducer and activator of transcription (STAT) ...
557-682 3.56e-18

Src homology 2 (SH2) domain found in signal transducer and activator of transcription (STAT) 5a proteins; STAT5 is a member of the STAT family of transcription factors. Two highly related proteins, STAT5a and STAT5b are encoded by separate genes, but are 90% identical at the amino acid level. Both STAT5a and STAT5b are ubiquitously expressed and functionally interchangeable. Mice lacking either STAT5a or STAT5b have mild defects in prolactin dependent mammary differentiation or sexually dimorphic growth hormone-dependent effects, respectively. Mice lacking both STAT5a and STAT5b exhibit a perinatal lethal phenotype and have multiple defects, including anemia and a virtual absence of B and T lymphocytes. STAT proteins mediate the signaling of cytokines and a number of growth factors from the receptors of these extracellular signaling molecules to the cell nucleus. STATs are specifically phosphorylated by receptor-associated Janus kinases, receptor tyrosine kinases, or cytoplasmic tyrosine kinases. The phosphorylated STAT molecules dimerize by reciprocal binding of their SH2 domains to the phosphotyrosine residues. These dimeric STATs translocate into the nucleus, bind to specific DNA sequences, and regulate the transcription of their target genes. However there are a number of unphosphorylated STATs that travel between the cytoplasm and nucleus and some STATs that exist as dimers in unstimulated cells that can exert biological functions independent of being activated. There are seven mammalian STAT family members which have been identified: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6. There are 6 conserved domains in STAT: N-terminal domain (NTD), coiled-coil domain (CCD), DNA-binding domain (DBD), alpha-helical linker domain (LD), SH2 domain, and transactivation domain (TAD). NTD is involved in dimerization of unphosphorylated STATs monomers and for the tetramerization between STAT1, STAT3, STAT4 and STAT5 on promoters with two or more tandem STAT binding sites. It also plays a role in promoting interactions with transcriptional co-activators such as CREB binding protein (CBP)/p300, as well as being important for nuclear import and deactivation of STATs involving tyrosine de-phosphorylation. CCD interacts with other proteins, such as IFN regulatory protein 9 (IRF-9/p48) with STAT1 and c-JUN with STAT3 and is also thought to participate in the negative regulation of these proteins. Distinct genes are bound to STATs via their DBD domain. This domain is also involved in nuclear translocation of activated STAT1 and STAT3 phosphorylated dimers upon cytokine stimulation. LD links the DNA-binding and SH2 domains and is important for the transcriptional activation of STAT1 in response to IFN-gamma. It also plays a role in protein-protein interactions and has also been implicated in the constitutive nucleocytoplasmic shuttling of unphosphorylated STATs in resting cells. The SH2 domain is necessary for receptor association and tyrosine phosphodimer formation. Residues within this domain may be particularly important for some cellular functions mediated by the STATs as well as residues adjacent to this domain. The TAD interacts with several proteins, namely minichromosome maintenance complex component 5 (MCM5), breast cancer 1 (BRCA1) and CBP/p300. TAD also contains a modulatory phosphorylation site that regulates STAT activity and is necessary for maximal transcription of a number of target genes. The conserved tyrosine residue present in the C-terminus is crucial for dimerization via interaction with the SH2 domain upon the interaction of the ligand with the receptor. STAT activation by tyrosine phosphorylation also determines nuclear import and retention, DNA binding to specific DNA elements in the promoters of responsive genes, and transcriptional activation of STAT dimers. In addition to the SH2 domain there is a coiled-coil domain, a DNA binding domain, and a transactivation domain in the STAT proteins. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198284  Cd Length: 140  Bit Score: 81.63  E-value: 3.56e-18
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 557 WIESILELIKKHLLPLWNDGCIMGFISKERERALLKDQQPGTFLLRFSESSReGAITFTWVERSqnggePD--FHAVEPY 634
Cdd:cd10421     1 WFDGVMEVLKKHHKPHWNDGAILGFVNKQQAHDLLINKPDGTFLLRFSDSEI-GGITIAWKFDS-----PDrnLWNLKPF 74
                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*...
gi 1862756640 635 TKKELSAVTFPDIIRNYkvmaaenipeNPLKYLYPNIDKDHAFGKYYS 682
Cdd:cd10421    75 TTRDFSIRSLADRLGDL----------NYLIYVFPDRPKDEVFSKYYT 112
STAT5_DBD cd16849
DNA-binding domain of Signal Transducer and Activator of Transcription 5 (STAT5); This family ...
317-475 5.77e-18

DNA-binding domain of Signal Transducer and Activator of Transcription 5 (STAT5); This family consists of the DNA-binding domain (DBD) of the STAT5 proteins (Signal Transducer and Activator of Transcription 5, or Signal Transduction And Transcription 4), which include STAT5A and STAT5B, both of which are >90% identical despite being encoded by separate genes. The DNA binding domain has an Ig-like fold. STAT5A and STAT5B regulate erythropoiesis, lymphopoiesis, and the maintenance of the hematopoietic stem cell population. STAT5A and STAT5B have overlapping and redundant functions; both isoforms can be activated by the same set of cytokines, but some cytokines preferentially activate either STAT5A or STAT5B, e.g. during pregnancy and lactation, STAT5A rather than STAT5B is required for the production of luminal progenitor cells from mammary stem cells and is essential for the differentiation of milk producing alveolar cells during pregnancy. STAT5 has been found to be constitutively phosphorylated in cancer cells, and therefore constantly activated, either by aberrant cell signaling expression or by mutations. It differentially regulates cellular behavior in human mammary carcinoma. Prolactin (PRL) in the prostate gland can induce growth and survival of prostate cancer cells and tissues through the activation of STAT5, its downstream target; PRL expression and STAT5 activation correlates with disease severity. STAT5A and STAT5B are central signaling molecules in leukemias driven by Abelson fusion tyrosine kinases, displaying unique nuclear shuttling mechanisms and having a key role in resistance of leukemic cells against treatment with tyrosine kinase inhibitors (TKI). In addition, STAT5A and STAT5B promote survival of leukemic stem cells. STAT5 is a key transcription factor for IL-3-mediated inhibition of RANKL-induced osteoclastogenesis via the induction of the expression of Id genes. Autosomal recessive STAT5B mutations are associated with severe growth failure, insulin-like growth factor (IGF) deficiency and growth hormone insensitivity (GHI) syndrome. STAT5B deficiency can lead to potentially fatal primary immunodeficiency.


Pssm-ID: 341087  Cd Length: 159  Bit Score: 81.78  E-value: 5.77e-18
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 317 FVVERQPcmpthpqrPLVLKTGVQFTVKLRLLVKlQELNYNL-------------KVKVLFDKDVNERNTVKGfrkfNIL 383
Cdd:cd16849     1 FIIEKQP--------PQVLKTQTRFAATVRLLVG-GKLNVHMnppqvkatiiseqQAKALLKNENITRNETSG----EIL 67
                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 384 gTHTKVMNMEESTnGSLAAEFRHLQLKEQKNAGTRTNEgplIVTEELHSLSFETQLCQPG--LVIDLETTSLPVVVISNV 461
Cdd:cd16849    68 -NNCGVMEYHQAT-GQLSVSFRNMSLKRIKRADKRGAE---SVTEEKFTILFQSQFSVGGneLVFQVWTLSLPVVVIVHG 142
                         170
                  ....*....|....
gi 1862756640 462 SQLPSGWASILWYN 475
Cdd:cd16849   143 NQESNATATVLWDN 156
STAT5_CCD cd16855
Coiled-coil domain of Signal Transducer and Activator of Transcription 5 (STAT5); This family ...
208-297 4.21e-12

Coiled-coil domain of Signal Transducer and Activator of Transcription 5 (STAT5); This family consists of the coiled-coil (alpha) domain of the STAT5 proteins (Signal Transducer and Activator of Transcription 5, or Signal Transduction And Transcription 5) which include STAT5A and STAT5B, both of which are >90% identical despite being encoded by separate genes. The coiled-coil domain (CCD) of STAT5A and STAT5B appears to be required for constitutive nuclear localization signals (NLS) function; small deletions within the CCD can abrogate nuclear import. Studies show that the CCD binds to the importin-alpha3 NLS adapter in most cells. STAT5A and STAT5B regulate erythropoiesis, lymphopoiesis, and the maintenance of the hematopoietic stem cell population. STAT5A and STAT5B have overlapping and redundant functions; both isoforms can be activated by the same set of cytokines, but some cytokines preferentially activate either STAT5A or STAT5B, e.g. during pregnancy and lactation, STAT5A rather than STAT5B is required for the production of luminal progenitor cells from mammary stem cells and is essential for the differentiation of milk producing alveolar cells during pregnancy. STAT5 has been found to be constitutively phosphorylated in cancer cells, and therefore constantly activated, either by aberrant cell signaling expression or by mutations. It differentially regulates cellular behavior in human mammary carcinoma. Prolactin (PRL) in the prostate gland can induce growth and survival of prostate cancer cells and tissues through the activation of STAT5, its downstream target; PRL expression and STAT5 activation correlates with disease severity. STAT5A and STAT5B are central signaling molecules in leukemias driven by Abelson fusion tyrosine kinases, displaying unique nuclear shuttling mechanisms and having a key role in resistance of leukemic cells against treatment with tyrosine kinase inhibitors (TKI). In addition, STAT5A and STAT5B promote survival of leukemic stem cells. STAT5 is a key transcription factor for IL-3-mediated inhibition of RANKL-induced osteoclastogenesis via the induction of the expression of Id genes. Autosomal recessive STAT5B mutations are associated with severe growth failure, insulin-like growth factor (IGF) deficiency and growth hormone insensitivity (GHI) syndrome. STAT5B deficiency can lead to potentially fatal primary immunodeficiency.


Pssm-ID: 341080 [Multi-domain]  Cd Length: 194  Bit Score: 65.75  E-value: 4.21e-12
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 208 NKRKEVVHKIIELLNVTELTQNALINDELVEWKRRQQSACIGGPPNACLDQLQNWFTIVAESLQQVRQQLKKLEELEQKY 287
Cdd:cd16855    86 QLRMELADKFKKTIQLLSKLQSRVLDEELIQWKRQQQLAGNGAPFESNLDTIQEWCESLAEIIWQNRQQIKRAERLKQKL 165
                          90
                  ....*....|
gi 1862756640 288 TYEHDPITKN 297
Cdd:cd16855   166 PIPLPPEQKD 175
SH2 pfam00017
SH2 domain;
578-622 5.95e-09

SH2 domain;


Pssm-ID: 425423 [Multi-domain]  Cd Length: 77  Bit Score: 53.37  E-value: 5.95e-09
                          10        20        30        40
                  ....*....|....*....|....*....|....*....|....*.
gi 1862756640 578 IMGFISK-ERERALLKDQQPGTFLLRFSESSrEGAITFTWVERSQN 622
Cdd:pfam00017   2 YHGKISRqEAERLLLNGKPDGTFLVRESEST-PGGYTLSVRDDGKV 46
STAT6_DBD cd16850
DNA-binding domain of Signal Transducer and Activator of Transcription 6 (STAT6); This family ...
317-475 1.11e-07

DNA-binding domain of Signal Transducer and Activator of Transcription 6 (STAT6); This family consists of the DNA-binding domain (DBD) of the STAT6 proteins (Signal Transducer and Activator of Transcription 6, or Signal Transduction And Transcription 6). The DNA binding domain has an Ig-like fold. STAT6 is essential for the functional responses of T helper 2 (Th2) lymphocyte mediated by interleukins IL-4 and IL-13. STAT6 almost exclusively mediates the expression of genes activated by these cytokines; IL-4 signaling regulates the expression of genes involved in immune and anti-inflammatory responses. Abnormal production of IL-4 and IL-13 play important roles in the pathogenesis of asthma where upregulation of the Th2 response mediated by IL-4/IL-13 is a main characteristic. STAT6 has a unique extended transactivation domain, not found in other STATs, through which it recruits p300/CBP and NCoA-1, two coactivators needed for transcriptional activation by IL-4. STAT6 activation is linked to Kaposi's sarcoma-associated herpesvirus (KSHV)-associated cancers such as primary effusion lymphoma, a cancerous proliferation of B cells. Studies show that Meningeal solitary fibrous tumor (SFT) and hemangiopericytoma (HPC) represent a histopathologic spectrum linked by STAT6 nuclear expression and recurrent somatic fusions of the two genes, NGFI-A-binding protein 2 (NAB2) and STAT6 (NAB2-STAT6), similar to their soft tissue counterparts. It is associated with local recurrence and late distance metastasis of brain tumors to extracranial sites.


Pssm-ID: 341088  Cd Length: 160  Bit Score: 52.19  E-value: 1.11e-07
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 317 FVVERQPcmpthpqrPLVLKTGVQFTVKLRLLVKLQELNYNLKVKVLFDKDVNERNTvkgfRKFNILG------------ 384
Cdd:cd16850     1 FLVEKQP--------PQVLKTQTKFQAGVRFLLGLRFLGAPAKPPLVRADMVTEKQA----RELSQPQgpgagnentgei 68
                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 385 THTKVMNMEESTNGSLAAEFRHLQLKEQKNAGTRTNEGpliVTEELHSLSFETQLC-QPG-LVIDLETTSLPVVVISNVS 462
Cdd:cd16850    69 INNTVPLENNITSKCCCATFKNLLLKKIKRCERKGSES---VTEEKCAVLFSADFTlGPGkLPIQLQALSLPVVVIVHGN 145
                         170
                  ....*....|...
gi 1862756640 463 QLPSGWASILWYN 475
Cdd:cd16850   146 QDNNAKATILWDN 158
STAT6_CCD cd16856
Coiled-coil domain of Signal Transducer and Activator of Transcription 6 (STAT6); This family ...
239-320 1.90e-07

Coiled-coil domain of Signal Transducer and Activator of Transcription 6 (STAT6); This family consists of the coiled-coil (alpha) domain of the STAT6 proteins (Signal Transducer and Activator of Transcription 6, or Signal Transduction And Transcription 6). SImilar to STAT3 and STAT5. the coiled-coil domain (CCD) of STAT6 is required for constitutive nuclear localization signals (NLS) function; small deletions within the CCD can abrogate nuclear import. Studies show that the CCD binds to the importin-alpha3 NLS adapter in most cells.STAT6 is essential for the functional responses of T helper 2 (Th2) lymphocyte mediated by interleukins IL-4 and IL-13. STAT6 almost exclusively mediates the expression of genes activated by these cytokines; IL-4 signaling regulates the expression of genes involved in immune and anti-inflammatory responses. Abnormal production of IL-4 and IL-13 play important roles in the pathogenesis of asthma where upregulation of the Th2 response mediated by IL-4/IL-13 is a main characteristic. STAT6 has a unique extended transactivation domain, not found in other STATs, through which it recruits p300/CBP and NCoA-1, two coactivators needed for transcriptional activation by IL-4. STAT6 activation is linked to Kaposi's sarcoma-associated herpesvirus (KSHV)-associated cancers such as primary effusion lymphoma, a cancerous proliferation of B cells. Studies show that Meningeal solitary fibrous tumor (SFT) and hemangiopericytoma (HPC) represent a histopathologic spectrum linked by STAT6 nuclear expression and recurrent somatic fusions of the two genes, NGFI-A-binding protein 2 (NAB2) and STAT6 (NAB2-STAT6), similar to their soft tissue counterparts. It is associated with local recurrence and late distance metastasis of brain tumors to extracranial sites.


Pssm-ID: 341081  Cd Length: 167  Bit Score: 51.31  E-value: 1.90e-07
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1862756640 239 WKRRQQSACIGGPPNACLDQLQNWFTIVAESLQQVRQQLKKLEELEQKYTYEHdpitknkqvLWDRTFSLFQQLIQSSFV 318
Cdd:cd16856    95 WKRQQQLAGNGAPFDENLSPLQTRCEQLVDVNFQLRQEVMLAGGELGSELLST---------LQERLNSLLQTLIQSSLV 165

                  ..
gi 1862756640 319 VE 320
Cdd:cd16856   166 VE 167
STAT1_TAZ2bind pfam12162
STAT1 TAZ2 binding domain; This domain family is found in eukaryotes, and is approximately 20 ...
723-747 6.15e-05

STAT1 TAZ2 binding domain; This domain family is found in eukaryotes, and is approximately 20 amino acids in length, and the family is found in association with pfam02865, pfam00017, pfam01017, pfam02864. This domain is the C terminal domain of STAT1. This domain binds selectively to the TAZ2 domain of CRB (CREB-binding protein). In this process it becomes a transcriptional activator and can initiate transcription of certain genes.


Pssm-ID: 432372  Cd Length: 23  Bit Score: 40.45  E-value: 6.15e-05
                          10        20
                  ....*....|....*....|....*
gi 1862756640 723 SRLQttDNLLPMSPEEFDEVSRIVG 747
Cdd:pfam12162   1 SRLQ--ENLMPMSPEDYGELERMVR 23
SH2 cd00173
Src homology 2 (SH2) domain; In general, SH2 domains are involved in signal transduction; they ...
580-608 1.81e-04

Src homology 2 (SH2) domain; In general, SH2 domains are involved in signal transduction; they bind pTyr-containing polypeptide ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites. They are present in a wide array of proteins including: adaptor proteins (Nck1, Crk, Grb2), scaffolds (Slp76, Shc, Dapp1), kinases (Src, Syk, Fps, Tec), phosphatases (Shp-1, Shp-2), transcription factors (STAT1), Ras signaling molecules (Ras-Gap), ubiquitination factors (c-Cbl), cytoskeleton regulators (Tensin), signal regulators (SAP), and phospholipid second messengers (PLCgamma), amongst others.


Pssm-ID: 198173 [Multi-domain]  Cd Length: 79  Bit Score: 40.52  E-value: 1.81e-04
                          10        20
                  ....*....|....*....|....*....
gi 1862756640 580 GFISKERERALLKDQQPGTFLLRFSESSR 608
Cdd:cd00173     5 GSISREEAERLLRGKPDGTFLVRESSSEP 33
SH2_SH2D2A_SH2D7 cd10349
Src homology 2 domain found in the SH2 domain containing protein 2A and 7 (SH2D2A and SH2D7); ...
580-622 2.68e-04

Src homology 2 domain found in the SH2 domain containing protein 2A and 7 (SH2D2A and SH2D7); SH2D2A and SH7 both contain a single SH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 199830  Cd Length: 77  Bit Score: 40.20  E-value: 2.68e-04
                          10        20        30        40
                  ....*....|....*....|....*....|....*....|...
gi 1862756640 580 GFISKERERALLKDQQPGTFLLRFSESsregAITFTWVERSQN 622
Cdd:cd10349     5 GFITRREAERLLEPKPQGCYLVRFSES----AVTFVLSYRSRT 43
SH2 smart00252
Src homology 2 domains; Src homology 2 domains bind phosphotyrosine-containing polypeptides ...
579-622 3.50e-04

Src homology 2 domains; Src homology 2 domains bind phosphotyrosine-containing polypeptides via 2 surface pockets. Specificity is provided via interaction with residues that are distinct from the phosphotyrosine. Only a single occurrence of a SH2 domain has been found in S. cerevisiae.


Pssm-ID: 214585 [Multi-domain]  Cd Length: 84  Bit Score: 39.90  E-value: 3.50e-04
                           10        20        30        40
                   ....*....|....*....|....*....|....*....|....*
gi 1862756640  579 MGFISKERERALLKDQQPGTFLLRFSESSREG-AITFTWVERSQN 622
Cdd:smart00252   5 HGFISREEAEKLLKNEGDGDFLVRDSESSPGDyVLSVRVKGKVKH 49
SH2_SH2D2A cd10416
Src homology 2 domain found in the SH2 domain containing protein 2A (SH2D2A); SH2D2A contains ...
571-621 2.33e-03

Src homology 2 domain found in the SH2 domain containing protein 2A (SH2D2A); SH2D2A contains a single SH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198279  Cd Length: 102  Bit Score: 38.10  E-value: 2.33e-03
                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1862756640 571 PLWndgcIMGFISKERERALLKDQQPGTFLLRFSESsregAITFTWVERSQ 621
Cdd:cd10416     7 PAW----FHGFITRREAERLLEPKPQGCYLVRFSES----AVTFVLTYRSR 49
SH2_SHA cd10338
Src homology 2 (SH2) domain found in SH2 adaptor proteins A (SHA) Signal transducers; Signal ...
571-606 5.26e-03

Src homology 2 (SH2) domain found in SH2 adaptor proteins A (SHA) Signal transducers; Signal transducing adaptor proteins are accessory to main proteins in a signal transduction pathway. These proteins lack intrinsic enzymatic activity, but mediate specific protein-protein interactions that drive the formation of protein complexes. Adaptor proteins usually contain several domains within their structure (e.g. SH2 and SH3 domains) which allow specific interactions with several other specific proteins. Not much is known about the SHA protein except that it is predicted to act as a transcription factor. Arabidopsis SHA pulled down a 120-kD tyrosine-phosphorylated protein in vitro. In addition to the SH2 domain there is a coiled-coil domain, a DNA binding domain, and a transactivation domain in the STAT proteins. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 198201  Cd Length: 106  Bit Score: 37.20  E-value: 5.26e-03
                          10        20        30
                  ....*....|....*....|....*....|....*.
gi 1862756640 571 PLWndgcIMGFISKERERALLKDQQPGTFLLRFSES 606
Cdd:cd10338    10 PKW----IEGFITKEEAERSLQGQVPGTFILRFPTS 41
SH2_SH2D7 cd10417
Src homology 2 domain found in the SH2 domain containing protein 7 (SH2D7); SH2D7 contains a ...
570-607 6.82e-03

Src homology 2 domain found in the SH2 domain containing protein 7 (SH2D7); SH2D7 contains a single SH2 domain. In general SH2 domains are involved in signal transduction. They typically bind pTyr-containing ligands via two surface pockets, a pTyr and hydrophobic binding pocket, allowing proteins with SH2 domains to localize to tyrosine phosphorylated sites.


Pssm-ID: 199832  Cd Length: 102  Bit Score: 36.79  E-value: 6.82e-03
                          10        20        30
                  ....*....|....*....|....*....|....*...
gi 1862756640 570 LPLWndgcIMGFISKERERALLKDQQPGTFLLRFSESS 607
Cdd:cd10417     6 LPPW----FHGFITRKQTEQLLRDKALGSFLIRLSDRA 39
 
Blast search parameters
Data Source: Precalculated data, version = cdd.v.3.21
Preset Options:Database: CDSEARCH/cdd   Low complexity filter: no  Composition Based Adjustment: yes   E-value threshold: 0.01

References:

  • Wang J et al. (2023), "The conserved domain database in 2023", Nucleic Acids Res.51(D)384-8.
  • Lu S et al. (2020), "The conserved domain database in 2020", Nucleic Acids Res.48(D)265-8.
  • Marchler-Bauer A et al. (2017), "CDD/SPARCLE: functional classification of proteins via subfamily domain architectures.", Nucleic Acids Res.45(D)200-3.
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