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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1867163805 523 WLDKILELVHDHLKDLWNDGRIMGFVSRSQERRLLKKTMSGTFLLRFSESSEGGITCSWVEHQDDDKVLIYSVQPYTKEV 602
Cdd:cd10373     1 WLDKILELVHDHLKDLWKDGRIMGFVSRNQERRLLKKTISGTFLLRFSETSEGGITCSWVEHQDDDKVLIYSVQPYTKEV 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1867163805 603 LQSLPLTEIIRHYQLLTEENIPENPLRFLYPRIPRDEAFGCYYQEKVNLQERRKYLKHRLIVVSNRQVDEL 673
Cdd:cd10373    81 LQSLPLTEIIRHYQLLTEENIPENPLRFLYPRIPRDEAFGCYYQEKVNLEEREKYLKHKLIVVSNRQVDEL 151

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1867163805 316 FVVETQPCMPQTPHRPLILKTGSKFTVRTRLLVRLQEGNESLTVEVSIDRNPPQLQGFRKFNILTSNQKTLTPEKGQSQG 395
Cdd:cd16846     1 FVVETQPCMPQPPRRPLVLKTNTQFSVRVRLLVKLPELNHSLKVEVSVDKNPPNSKGFRRFNILGTNNKTLNMDEGQSGG 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1867163805 396 LIWDFGYLTLVEQRSGGSGKGSNKGPLGVTEELHIISFTVKYTYQGLKQEL 446
Cdd:cd16846    81 LVADFRHLTLKEQKVGGGGKGSNEGSLSVTEELHLITFTTDYKYQGLKVKL 131

Signal transducer and activator of transcription 2 C terminal; This domain family is found in eukaryotes, and is approximately 60 amino acids in length. The family is found in association with pfam02865, pfam00017, pfam01017, pfam02864. There is a conserved DLP sequence motif. STATs are involved in transcriptional regulation and are the only regulators known to be modulated by tyrosine phosphorylation. STAT2 forms a trimeric complex with STAT1 and IRF-9 (Interferon Regulatory Factor 9), on activation of the cell by interferon, which is called ISGF3 (Interferon-stimulated gene factor 3). The C terminal domain of STAT2 contains a nuclear export signal (NES) which allows export of STAT2 into the cytoplasm along with any complexed molecules.

                          10        20        30        40        50
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 1867163805 751 QPVPEPDLPCDLRHLNTEPMEIFRNCVKIEEIMPNGDPLLAGQNTVDEVYVSRPS 805
Cdd:pfam12188   1 QPVPEPDLPQDLQHLNTEDMEIFRNNVNIEEIMPNGDPLLAGQNTGDEAYISCPS 55

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1867163805 523 WLDKILELVHDHLKDLWNDGRIMGFVSRSQERRLLKKTMSGTFLLRFSESSEGGITCSWVEHQDDDKVLIYSVQPYTKEV 602
Cdd:cd10373     1 WLDKILELVHDHLKDLWKDGRIMGFVSRNQERRLLKKTISGTFLLRFSETSEGGITCSWVEHQDDDKVLIYSVQPYTKEV 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1867163805 603 LQSLPLTEIIRHYQLLTEENIPENPLRFLYPRIPRDEAFGCYYQEKVNLQERRKYLKHRLIVVSNRQVDEL 673
Cdd:cd10373    81 LQSLPLTEIIRHYQLLTEENIPENPLRFLYPRIPRDEAFGCYYQEKVNLEEREKYLKHKLIVVSNRQVDEL 151

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1867163805 316 FVVETQPCMPQTPHRPLILKTGSKFTVRTRLLVRLQEGNESLTVEVSIDRNPPQLQGFRKFNILTSNQKTLTPEKGQSQG 395
Cdd:cd16846     1 FVVETQPCMPQPPRRPLVLKTNTQFSVRVRLLVKLPELNHSLKVEVSVDKNPPNSKGFRRFNILGTNNKTLNMDEGQSGG 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1867163805 396 LIWDFGYLTLVEQRSGGSGKGSNKGPLGVTEELHIISFTVKYTYQGLKQEL 446
Cdd:cd16846    81 LVADFRHLTLKEQKVGGGGKGSNEGSLSVTEELHLITFTTDYKYQGLKVKL 131

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.

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1867163805    2 AQWEMLQNLDSPFQDQLHQLYShSLLPVDIRQYLAVWIEDQNWQEAALgsDDSKATMLFFHFLDQLNYECGRCSQDpESL 81
Cdd:smart00964   1 SQWAQLQQLDSKFLEQVQQLYG-DNFPMELRHYLADWIESQDWELAAN--DEAQATRLFHNLLEQLDQQLSRFSQE-SNF 76

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....
gi 1867163805   82 LLQHNLRKFCRDIQP-FSQDPTQLAEMIFNLLLEEKRILIQAQR 124
Cdd:smart00964  77 LLKHNLRHIKSNLQSlYQENPLELARIIRNILQEERRILAEASR 120

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1867163805 320 TQPcmpqtphrPLILKTGSKFTVRTRLLVRLQ---EGNESLTVEVSID---RNPPQLQGFRKFNILT--SNQKTLTPEKG 391
Cdd:pfam02864   1 KQP--------PQVLKTNTKFSVTVRLLVGLPlniELNPQVKVKIVSEkqaRELQQIKGFRKFNISGeiLNNKALLEYES 72

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1867163805 392 QSQGLIWDFGYLTLVEQRSGGSGKgsnkgPLGVTEELHIISFTVKYTYQGLKQELKN 448
Cdd:pfam02864  73 QNGGLSAEFRNLSLKEIKRGERKG-----SLSVTEEKFALLFETQFTLGGLVFDLWT 124

SH2 domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1867163805 544 IMGFVSRSQ-ERRLLKKTMSGTFLLRFSESSEGGITCSWVehqDDDKVLIYSVQP--------YTKEVLQSLPltEIIRH 614
Cdd:pfam00017   2 YHGKISRQEaERLLLNGKPDGTFLVRESESTPGGYTLSVR---DDGKVKHYKIQStdnggyyiSGGVKFSSLA--ELVEH 76

                  .
gi 1867163805 615 Y 615
Cdd:pfam00017  77 Y 77

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1867163805 523 WLDKILELVHDHLKDLWNDGRIMGFVSRSQERRLLKKTMSGTFLLRFSESSEGGITCSWVEHQDDDKVLIYSVQPYTKEV 602
Cdd:cd10373     1 WLDKILELVHDHLKDLWKDGRIMGFVSRNQERRLLKKTISGTFLLRFSETSEGGITCSWVEHQDDDKVLIYSVQPYTKEV 80

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 1867163805 603 LQSLPLTEIIRHYQLLTEENIPENPLRFLYPRIPRDEAFGCYYQEKVNLQERRKYLKHRLIVVSNRQVDEL 673
Cdd:cd10373    81 LQSLPLTEIIRHYQLLTEENIPENPLRFLYPRIPRDEAFGCYYQEKVNLEEREKYLKHKLIVVSNRQVDEL 151

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1867163805 316 FVVETQPCMPQTPHRPLILKTGSKFTVRTRLLVRLQEGNESLTVEVSIDRNPPQLQGFRKFNILTSNQKTLTPEKGQSQG 395
Cdd:cd16846     1 FVVETQPCMPQPPRRPLVLKTNTQFSVRVRLLVKLPELNHSLKVEVSVDKNPPNSKGFRRFNILGTNNKTLNMDEGQSGG 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1867163805 396 LIWDFGYLTLVEQRSGGSGKGSNKGPLGVTEELHIISFTVKYTYQGLKQEL 446
Cdd:cd16846    81 LVADFRHLTLKEQKVGGGGKGSNEGSLSVTEELHLITFTTDYKYQGLKVKL 131

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1867163805 523 WLDKILELVHDHLKDLWNDGRIMGFVSRSQERRLLKKTMSGTFLLRFSESSEGGITCSWVEHQDDDKVLIYSVQPYTKEV 602
Cdd:cd10375     1 WLEAILDLIKKHILPLWIDGYIMGFVSKEKERLLLKDKMPGTFLLRFSESHLGGITFTWVDQSENGEVRFHSVEPYNKGR 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*...
gi 1867163805 603 LQSLPLTEIIRHYQLLTEENIPENPLRFLYPRIPRDEAFGCYYQEKVN 650
Cdd:cd10375    81 LSALPFADILRDYKVIMAENIPENPLKYLYPDIPKDKAFGKHYSSQPC 128

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1867163805 523 WLDKILELVHDHLKDLWNDGRIMGFVSRSQERRLLKKTMSGTFLLRFSESSEGGITCSWVEHQDDDKVLIYSVQPYTKEV 602
Cdd:cd09919     1 WFFAIMLLTKRHLLKLWQDGLIMGFISKEEAEDLLKKKPPGTFLLRFSDSELGGITIAWVNEDPDGQSQVIHLQPYTKKD 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*
gi 1867163805 603 LQSLPLTEIIRHYQllteenipenPLRFLYPRIPRDEAFGCYYQE 647
Cdd:cd09919    81 LDIRSLADRIRDLP----------QLVYLYPDIPKDEAFGKYYSP 115

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1867163805 520 FWTWLDKILELVHDHLKDLWNDGRIMGFVSRSQERRLLKKTMSGTFLLRFSESS-EGGITCSWVEHQDDDKVLIYSVQPY 598
Cdd:cd10374     8 FWVWLDNIIDLVKKYILALWNEGYIMGFISKERERAILSTKPPGTFLLRFSESSkEGGVTFTWVEKDISGKTQIQSVEPY 87

                          90       100       110       120       130       140       150
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 1867163805 599 TKEVLQSLPLTEIIRHYQLLTEENIPENPLRFLYPRIPRDEAFGCYYQEKVNLQER------RKYLKHRLIVVS 666
Cdd:cd10374    88 TKQQLNNMSFAEIIMGYKIMDATNILVSPLVYLYPDIPKEEAFGKYCRPESQEHPEadpgsaAPYLKTKFICVT 161

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1867163805 320 TQPcmpqtphrPLILKTGSKFTVRTRLLVRLQ---EGNESLTVEVSID---RNPPQLQGFRKFNILT--SNQKTLTPEKG 391
Cdd:pfam02864   1 KQP--------PQVLKTNTKFSVTVRLLVGLPlniELNPQVKVKIVSEkqaRELQQIKGFRKFNISGeiLNNKALLEYES 72

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*..
gi 1867163805 392 QSQGLIWDFGYLTLVEQRSGGSGKgsnkgPLGVTEELHIISFTVKYTYQGLKQELKN 448
Cdd:pfam02864  73 QNGGLSAEFRNLSLKEIKRGERKG-----SLSVTEEKFALLFETQFTLGGLVFDLWT 124

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1867163805 316 FVVETQPCMPQTPHRPLILKTGSKFTVRTRLLVRLQEGNESLTVEVSIDRNPPQ---LQGFRKFNILTSNQKTLTPEKGQ 392
Cdd:cd16847     1 FVVERQPCMPMHPDRPLVIKTGVQFTTKVRLLVKFPELNYQLKIKVCIDKDSGDvaaLRGSRKFNILGTNTKVMNMEESN 80

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*....
gi 1867163805 393 SQGLIWDFGYLTLVEQRSGGSGKGSNKGPLGVTEELHIISFTVKYTYQGLKQELKNQQF 451
Cdd:cd16847    81 NGSLSAEFKHLTLREQRCGNGGRANCDASLIVTEELHLITFETEVYHQGLKIDLETHSL 139

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1867163805 523 WLDKILELVHDHLKDLWNDGRIMGFVSRSQERRLLKKTMSGTFLLRFSESSEGGITCSWVEHQDDDKVLIYSVQPYTKEV 602
Cdd:cd10377     1 WFDGVLDLTKRCLRSYWSDRLIIGFISKQYVTSLLLNEPDGTFLLRFSDSEIGGITIAHVIRGQDGSPQIENIQPFSAKD 80

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|....*.
gi 1867163805 603 LQSLPLTEIIRhyqllteeNIPEnpLRFLYPRIPRDEAFGCYYQEK 648
Cdd:cd10377    81 LSIRSLGDRIR--------DLAQ--LKNLYPKKPKDEAFRSHYKPE 116

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1867163805 316 FVVETQPCMPQTPHRPLILKTGSKFTVRTRLLVRLQEGNESLTVEVSIDRNppqlqgfRKFNILTSNQKTLTPEKGQSQG 395
Cdd:cd16848     1 FVVERQPCMPTHPQRPMVLKTLIQFTVKLRLLIKLPELNYQIRVKATIDNN-------RRFVLCGTHVKAMNLEESVNGS 73

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|.
gi 1867163805 396 LIWDFGYLTlVEQRSGGSGKGSNKGPLGVTEELHIISFTVKYTYQGLKQEL 446
Cdd:cd16848    74 LSVEFRHLQ-PKEMKPSGGSKGNEGPHMVTEELHSISFETQFSLYGLTIDL 123

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1867163805 142 QHEIESRILDLRAMMEKLVKSISQLKDQQDVFCFRYK-IQakgktpSLDPHQTKEQKI------LQETLNELDKRRKEVL 214
Cdd:cd16854     1 QRNVEHKVSAIKNSVQMTDQDTKYLEDLQDEFDFRYKtIQ------TMDQGDKNSILMkqevttLQEMLNSLDFKRKEAL 74

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1867163805 215 DASKALLGRLTTLI-ELLLPKLEEWKAQQQKACIRAPIDHGLEQLETWFTAGAKLLFHLRQLLKELKGLSCLVSYQDDPL 293
Cdd:cd16854    75 SKMTQIINEIDLLMsSMLTEELKDWKRRQQIACIGGPLHGGLDQLQNWFTLLAESLFQLRRQLEKLDELSTKVTYEGDPI 154

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1867163805 523 WLDKILELVHDHLKDLWNDGRIMGFVSRSQERRLLKKTMSGTFLLRFSESSEGGITCSWvEHQDDDKVLiYSVQPYTKEV 602
Cdd:cd10376     1 WFDGVMEVLKKHLKPHWNDGAILGFVNKQQAHDLLINKPDGTFLLRFSDSEIGGITIAW-KFDSPDRAL-WNLMPFTTRD 78

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 1867163805 603 LQSLPLTEIIRHYqllteenipeNPLRFLYPRIPRDEAFGCYY 645
Cdd:cd10376    79 FSIRSLADRLGDL----------NYLIYVFPDRPKDEVFSKYY 111

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1867163805 523 WLDKILELVHDHLKDLWNDGRIMGFVSRSQERRLLKKTMSGTFLLRFSESSEGGITCSWVEHQDDDKvlIYSVQPYTKEV 602
Cdd:cd10421     1 WFDGVMEVLKKHHKPHWNDGAILGFVNKQQAHDLLINKPDGTFLLRFSDSEIGGITIAWKFDSPDRN--LWNLKPFTTRD 78

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 1867163805 603 LQSLPLTEIIRHYqllteenipeNPLRFLYPRIPRDEAFGCYY 645
Cdd:cd10421    79 FSIRSLADRLGDL----------NYLIYVFPDRPKDEVFSKYY 111

SH2 domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1867163805 544 IMGFVSRSQ-ERRLLKKTMSGTFLLRFSESSEGGITCSWVehqDDDKVLIYSVQP--------YTKEVLQSLPltEIIRH 614
Cdd:pfam00017   2 YHGKISRQEaERLLLNGKPDGTFLVRESESTPGGYTLSVR---DDGKVKHYKIQStdnggyyiSGGVKFSSLA--ELVEH 76

                  .
gi 1867163805 615 Y 615
Cdd:pfam00017  77 Y 77

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1867163805 143 HEIESRILDLRAMMEKLVKSISQLKDQQDVFCFRY----KIQAKGKTPSLDP-----------HQTKEQ--KILQETLNE 205
Cdd:cd16855     4 LEIRQQLEELRQRTQETENDLRNLQQKQESFVIQYqesqKIQAQLQQLQQQPqnerieleqqlQQQKEQleQLLNAKAQE 83

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 1867163805 206 LDKRRKEVLDASKALLGRLTTLIELLLPK-LEEWKAQQQKACIRAPIDHGLEQLETWFTAGAKLLFHLRQLLKEL----- 279
Cdd:cd16855    84 LLQLRMELADKFKKTIQLLSKLQSRVLDEeLIQWKRQQQLAGNGAPFESNLDTIQEWCESLAEIIWQNRQQIKRAerlkq 163

                         170       180       190
                  ....*....|....*....|....*....|....
gi 1867163805 280 KGLSCLVSYQDDPLtkgvDLRNAQVTELLQRLLH 313
Cdd:cd16855   164 KLPIPLPPEQKDML----PILNKQITDLLSSLVT 193

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.

                          10        20        30
                  ....*....|....*....|....*....|..
gi 1867163805 546 GFVSRSQERRLLKKTMSGTFLLRFSESSEGGI 577
Cdd:cd10349     5 GFITRREAERLLEPKPQGCYLVRFSESAVTFV 36