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 414073168 558 WLDKILDLVHDHLKDLWNDGRIMGFVSRSQERRLLKKTISGTFLLRFSETSEGGITCSWVEHQDDDKVLIYSVQPFTKEV 637
Cdd:cd10373    1 WLDKILELVHDHLKDLWKDGRIMGFVSRNQERRLLKKTISGTFLLRFSETSEGGITCSWVEHQDDDKVLIYSVQPYTKEV 80

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 414073168 638 LQSLPLTKIIRHYQLLTEENIPENPLCFLYPRIPRDEAFGCYYEDKVNLQERRKYLKHKLIVVSNRQVDEL 708
Cdd:cd10373   81 LQSLPLTEIIRHYQLLTEENIPENPLRFLYPRIPRDEAFGCYYQEKVNLEEREKYLKHKLIVVSNRQVDEL 151

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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 414073168 141 QQPEIESRILELRVMMEKLVKSISQLKDQQDVFCFRYKTHTLARTASLDPHQIRQQQLLQETLNELDKRRKEVLDASKAL 220
Cdd:cd16852    1 RQHEIEKRINDLKTRIQCLEHSIRQLEDLQDTFDFKYKTHTMDKSTSPDDKQTKQQQILQGMLNELDRFRKEVLSKMKVL 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 414073168 221 LGRLTTLTELLLPKLEEWKVQQQKACIGSREDGGLElsQLEKWFTDGAKLLFHLRQLLKELKGLSHLVSYHHDPLTTGVD 300
Cdd:cd16852   81 LGRRDTLRELLLEELVEWKRRQQKACIGAPDDTSLE--QLEKWFTKVAECLFQLRKFLKKLEELMGKVSYEHDPLKKQKP 158

                        170
                 ....*....|....
gi 414073168 301 LREAQVTELLQRLL 314
Cdd:cd16852  159 LLQQRVDELLTSLL 172

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 414073168  790 QPVPEPDLPHDLEHLNTEEMEIFRNSMNIEDIMPNGDPLLADQNTVDEAYILHPS 844
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 414073168 558 WLDKILDLVHDHLKDLWNDGRIMGFVSRSQERRLLKKTISGTFLLRFSETSEGGITCSWVEHQDDDKVLIYSVQPFTKEV 637
Cdd:cd10373    1 WLDKILELVHDHLKDLWKDGRIMGFVSRNQERRLLKKTISGTFLLRFSETSEGGITCSWVEHQDDDKVLIYSVQPYTKEV 80

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 414073168 638 LQSLPLTKIIRHYQLLTEENIPENPLCFLYPRIPRDEAFGCYYEDKVNLQERRKYLKHKLIVVSNRQVDEL 708
Cdd:cd10373   81 LQSLPLTEIIRHYQLLTEENIPENPLRFLYPRIPRDEAFGCYYQEKVNLEEREKYLKHKLIVVSNRQVDEL 151

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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 414073168 141 QQPEIESRILELRVMMEKLVKSISQLKDQQDVFCFRYKTHTLARTASLDPHQIRQQQLLQETLNELDKRRKEVLDASKAL 220
Cdd:cd16852    1 RQHEIEKRINDLKTRIQCLEHSIRQLEDLQDTFDFKYKTHTMDKSTSPDDKQTKQQQILQGMLNELDRFRKEVLSKMKVL 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 414073168 221 LGRLTTLTELLLPKLEEWKVQQQKACIGSREDGGLElsQLEKWFTDGAKLLFHLRQLLKELKGLSHLVSYHHDPLTTGVD 300
Cdd:cd16852   81 LGRRDTLRELLLEELVEWKRRQQKACIGAPDDTSLE--QLEKWFTKVAECLFQLRKFLKKLEELMGKVSYEHDPLKKQKP 158

                        170
                 ....*....|....
gi 414073168 301 LREAQVTELLQRLL 314
Cdd:cd16852  159 LLQQRVDELLTSLL 172

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 414073168     2 AQWEMLQNLDSPFQDQLHQLYtNSLLPVDIRQYLAVWIEDQNWQEAALgkDDSQANMLFFHFLDQLKYECGRCSQDpECL 81
Cdd:smart00964   1 SQWAQLQQLDSKFLEQVQQLY-GDNFPMELRHYLADWIESQDWELAAN--DEAQATRLFHNLLEQLDQQLSRFSQE-SNF 76

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....
gi 414073168    82 LLQHNLRKFCRDIQAFPQG-PTQLAEMIFNLLLEEKRILIQAQR 124
Cdd:smart00964  77 LLKHNLRHIKSNLQSLYQEnPLELARIIRNILQEERRILAEASR 120

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 414073168    2 AQWEMLQNLDSPFQDQLHQLYTNSLlPVDIRQYLAVWIEDQNWQEAALgkDDSQANMLFFHFLDQLKYECGRCSQDpECL 81
Cdd:pfam02865   1 SLWAQLQQLDGEALEQVQQLYGDHF-PIEVRHYLAQWIESQDWEDAAQ--DESLATVLFHALLSELDSQASRFVQE-DNF 76

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 414073168   82 LLQHNLRKFCRDIQA-FPQGPTQLAEMIFNLLLEEKRILIQAQ 123
Cdd:pfam02865  77 LLKHKLREIAKNLQSrYQENPLELARIIRNCLREERRILQEAE 119

SH2 domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 414073168  579 IMGFVSRSQ-ERRLLKKTISGTFLLRFSETSEGGITCSWVehqDDDKVLIYSVQP--------FTKEVLQSLPLtkIIRH 649
Cdd:pfam00017   2 YHGKISRQEaERLLLNGKPDGTFLVRESESTPGGYTLSVR---DDGKVKHYKIQStdnggyyiSGGVKFSSLAE--LVEH 76

                  .
gi 414073168  650 Y 650
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 414073168 558 WLDKILDLVHDHLKDLWNDGRIMGFVSRSQERRLLKKTISGTFLLRFSETSEGGITCSWVEHQDDDKVLIYSVQPFTKEV 637
Cdd:cd10373    1 WLDKILELVHDHLKDLWKDGRIMGFVSRNQERRLLKKTISGTFLLRFSETSEGGITCSWVEHQDDDKVLIYSVQPYTKEV 80

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 414073168 638 LQSLPLTKIIRHYQLLTEENIPENPLCFLYPRIPRDEAFGCYYEDKVNLQERRKYLKHKLIVVSNRQVDEL 708
Cdd:cd10373   81 LQSLPLTEIIRHYQLLTEENIPENPLRFLYPRIPRDEAFGCYYQEKVNLEEREKYLKHKLIVVSNRQVDEL 151

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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 414073168 141 QQPEIESRILELRVMMEKLVKSISQLKDQQDVFCFRYKTHTLARTASLDPHQIRQQQLLQETLNELDKRRKEVLDASKAL 220
Cdd:cd16852    1 RQHEIEKRINDLKTRIQCLEHSIRQLEDLQDTFDFKYKTHTMDKSTSPDDKQTKQQQILQGMLNELDRFRKEVLSKMKVL 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 414073168 221 LGRLTTLTELLLPKLEEWKVQQQKACIGSREDGGLElsQLEKWFTDGAKLLFHLRQLLKELKGLSHLVSYHHDPLTTGVD 300
Cdd:cd16852   81 LGRRDTLRELLLEELVEWKRRQQKACIGAPDDTSLE--QLEKWFTKVAECLFQLRKFLKKLEELMGKVSYEHDPLKKQKP 158

                        170
                 ....*....|....
gi 414073168 301 LREAQVTELLQRLL 314
Cdd:cd16852  159 LLQQRVDELLTSLL 172

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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 414073168 558 WLDKILDLVHDHLKDLWNDGRIMGFVSRSQERRLLKKTISGTFLLRFSETS-EGGITCSWVEH-QDDDKVLIYSVQPFTK 635
Cdd:cd10372    1 WIESILELIKKHLLSLWNDGCIMGFISKERERALLKDQQPGTFLLRFSESSrEGAITFTWVERsQNGGEPDFHAVEPYTK 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|...
gi 414073168 636 EVLQSLPLTKIIRHYQLLTEENIPENPLCFLYPRIPRDEAFGCYYEDKVNLQE 688
Cdd:cd10372   81 KELSAVTFPDIIRNYKVMAAENIPENPLKYLYPNIDKDHAFGKYYSRPKEAPE 133

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 414073168     2 AQWEMLQNLDSPFQDQLHQLYtNSLLPVDIRQYLAVWIEDQNWQEAALgkDDSQANMLFFHFLDQLKYECGRCSQDpECL 81
Cdd:smart00964   1 SQWAQLQQLDSKFLEQVQQLY-GDNFPMELRHYLADWIESQDWELAAN--DEAQATRLFHNLLEQLDQQLSRFSQE-SNF 76

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....
gi 414073168    82 LLQHNLRKFCRDIQAFPQG-PTQLAEMIFNLLLEEKRILIQAQR 124
Cdd:smart00964  77 LLKHNLRHIKSNLQSLYQEnPLELARIIRNILQEERRILAEASR 120

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 414073168 555 FWTWLDKILDLVHDHLKDLWNDGRIMGFVSRSQERRLLKKTISGTFLLRFSETS-EGGITCSWVEHQDDDKVLIYSVQPF 633
Cdd:cd10374    8 FWVWLDNIIDLVKKYILALWNEGYIMGFISKERERAILSTKPPGTFLLRFSESSkEGGVTFTWVEKDISGKTQIQSVEPY 87

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....
gi 414073168 634 TKEVLQSLPLTKIIRHYQLLTEENIPENPLCFLYPRIPRDEAFGCY------YEDKVNLQERRKYLKHKLIVVS 701
Cdd:cd10374   88 TKQQLNNMSFAEIIMGYKIMDATNILVSPLVYLYPDIPKEEAFGKYcrpesqEHPEADPGSAAPYLKTKFICVT 161

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 414073168 318 FVVETQPCMPQTPHRPLILRTGSKFTVRTRLLVRLQEGNETLTAEVFIDRNPLQS---QGFRKFNILTSNRKTLTPEKGQ 394
Cdd:cd16847    1 FVVERQPCMPMHPDRPLVIKTGVQFTTKVRLLVKFPELNYQLKIKVCIDKDSGDVaalRGSRKFNILGTNTKVMNMEESN 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 414073168 395 SQGLIWDFSYLTLLEQRSGGSGKGNNKGLLGVTEELHIISFTVKYTYQGLKQELKTDTLPVVIISNMNQLSIAWASVLWF 474
Cdd:cd16847   81 NGSLSAEFKHLTLREQRCGNGGRANCDASLIVTEELHLITFETEVYHQGLKIDLETHSLPVVVISNICQMPNAWASILWY 160

                 ....
gi 414073168 475 NLLS 478
Cdd:cd16847  161 NMLT 164

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 414073168 318 FVVETQPCMPQTPHRPLILRTGSKFTVRTRLLVRLQEGNETLTAEVFIDRNplqsqgfRKFNILTSNRKTLTPEKGQSQG 397
Cdd:cd16848    1 FVVERQPCMPTHPQRPMVLKTLIQFTVKLRLLIKLPELNYQIRVKATIDNN-------RRFVLCGTHVKAMNLEESVNGS 73

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 414073168 398 LIWDFSYLTLlEQRSGGSGKGNNKGLLGVTEELHIISFTVKYTYQGLKQELKTDTLPVVIISNMNQLSIAWASVLWFNLL 477
Cdd:cd16848   74 LSVEFRHLQP-KEMKPSGGSKGNEGPHMVTEELHSISFETQFSLYGLTIDLETSSLPVVMISNVSQLPNAWASIIWYNLL 152

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.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 414073168    2 AQWEMLQNLDSPFQDQLHQLYTNSLlPVDIRQYLAVWIEDQNWQEAALgkDDSQANMLFFHFLDQLKYECGRCSQDpECL 81
Cdd:pfam02865   1 SLWAQLQQLDGEALEQVQQLYGDHF-PIEVRHYLAQWIESQDWEDAAQ--DESLATVLFHALLSELDSQASRFVQE-DNF 76

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|...
gi 414073168   82 LLQHNLRKFCRDIQA-FPQGPTQLAEMIFNLLLEEKRILIQAQ 123
Cdd:pfam02865  77 LLKHKLREIAKNLQSrYQENPLELARIIRNCLREERRILQEAE 119

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 414073168 558 WLDKILDLVHDHLKDLWNDGRIMGFVSRSQERRLLKKTISGTFLLRFSETSEGGITCSWVEHQDDDKVLIYSVQPFTKEV 637
Cdd:cd10377    1 WFDGVLDLTKRCLRSYWSDRLIIGFISKQYVTSLLLNEPDGTFLLRFSDSEIGGITIAHVIRGQDGSPQIENIQPFSAKD 80

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 414073168 638 LQSLPLTKIIRHYQLLTeenipenplcFLYPRIPRDEAFGCYY 680
Cdd:cd10377   81 LSIRSLGDRIRDLAQLK----------NLYPKKPKDEAFRSHY 113

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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 414073168 558 WLDKILDLVHDHLKDLWNDGRIMGFVSRSQERRLLKKTISGTFLLRFSETSEGGITCSWveHQDDDKVLIYSVQPFTKEV 637
Cdd:cd10420    1 WFDGVMEVLKKHLKPHWNDGAILGFVNKQQAHDLLINKPDGTFLLRFSDSEIGGITIAW--KFDSQERMFWNLMPFTTRD 78

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|...
gi 414073168 638 LQSLPLTKIIRHYQLLTeenipenplcFLYPRIPRDEAFGCYY 680
Cdd:cd10420   79 FSIRSLADRLGDLNYLI----------YVFPDRPKDEVYSKYY 111

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 414073168 166 LKDQQDVFCFRYKTHTLARTASLDPHQIRQQQL-LQETLNELDKRRKEVLDA-SKALLGRLTTLTELLLPKLEEWKVQQQ 243
Cdd:cd16854   25 LEDLQDEFDFRYKTIQTMDQGDKNSILMKQEVTtLQEMLNSLDFKRKEALSKmTQIINEIDLLMSSMLTEELKDWKRRQQ 104

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 414073168 244 KACIGSREDGGLElsQLEKWFTDGAKLLFHLRQLLKELKGLSHLVSYHHDPLTTGVDLREAQVTELLQRLL 314
Cdd:cd16854  105 IACIGGPLHGGLD--QLQNWFTLLAESLFQLRRQLEKLDELSTKVTYEGDPIPLQRPQLLERVTFLIYNLF 173

SH2 domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 414073168  579 IMGFVSRSQ-ERRLLKKTISGTFLLRFSETSEGGITCSWVehqDDDKVLIYSVQP--------FTKEVLQSLPLtkIIRH 649
Cdd:pfam00017   2 YHGKISRQEaERLLLNGKPDGTFLVRESESTPGGYTLSVR---DDGKVKHYKIQStdnggyyiSGGVKFSSLAE--LVEH 76

                  .
gi 414073168  650 Y 650
Cdd:pfam00017  77 Y 77

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.

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gi 414073168 141 QQPEIESRilELRVMMEKLVKSISQLKDQQDVFCFRYKTHTLARTASLDPHQ----IRQ-QQLLQETLNELDKRRKEVL- 214
Cdd:cd16853    4 QMLEQHLQ--DVRKRVQDLEQKMKVVENLQDDFDFNYKTLKSQGDMQDLNGNnqsvTRQkMQQLEQMLTALDQMRRQIVs 81

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 414073168 215 DASKALLGRLTTLTELLLPKLEEWKVQQQKACIGSREDggLELSQLEKWFTDGAKLLFHLRQLLKELKGLSHLVSYHHDP 294
Cdd:cd16853   82 ELAGLLSAMEYVQKNLTDEELADWKRRQQIACIGGPPN--ICLDRLENWITSLAESQLQTRQQIKKLEELQQKVSYKGDP 159

                        170       180
                 ....*....|....*....|
gi 414073168 295 LTTGVDLREAQVTELLQRLL 314
Cdd:cd16853  160 IVQHRPMLEERIVELFRNLM 179

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.

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                 ....*....|....*....|....*....|....*....|.
gi 414073168 581 GFVSRSQERRLLKKTISGTFLLRFSETSEGGITCSWVEHQD 621
Cdd:cd00173    5 GSISREEAERLLRGKPDGTFLVRESSSEPGDYVLSVRSGDG 45

Src homology 2 (SH2) domain found in Abelson murine lymphosarcoma virus (ABL) proteins; ABL-family proteins are highly conserved tyrosine kinases. Each ABL protein contains an SH3-SH2-TK (Src homology 3-Src homology 2-tyrosine kinase) domain cassette, which confers autoregulated kinase activity and is common among nonreceptor tyrosine kinases. Several types of posttranslational modifications control ABL catalytic activity, subcellular localization, and stability, with consequences for both cytoplasmic and nuclear ABL functions. Binding partners provide additional regulation of ABL catalytic activity, substrate specificity, and downstream signaling. By combining this cassette with actin-binding and -bundling domain, ABL proteins are capable of connecting phosphoregulation with actin-filament reorganization. Vertebrate paralogs, ABL1 and ABL2, have evolved to perform specialized functions. ABL1 includes nuclear localization signals and a DNA binding domain which is used to mediate DNA damage-repair functions, while ABL2 has additional binding capacity for actin and for microtubules to enhance its cytoskeletal remodeling functions. SH2 is involved in several autoinhibitory mechanism that constrain the enzymatic activity of the ABL-family kinases. In one mechanism SH2 and SH3 cradle the kinase domain while a cap sequence stabilizes the inactive conformation resulting in a locked inactive state. Another involves phosphatidylinositol 4,5-bisphosphate (PIP2) which binds the SH2 domain through residues normally required for phosphotyrosine binding in the linker segment between the SH2 and kinase domains. The SH2 domain contributes to ABL catalytic activity and target site specificity. It is thought that the ABL catalytic site and SH2 pocket have coevolved to recognize the same sequences. Recent work now supports a hierarchical processivity model in which the substrate target site most compatible with ABL kinase domain preferences is phosphorylated with greatest efficiency. If this site is compatible with the ABL SH2 domain specificity, it will then reposition and dock in the SH2 pocket. This mechanism also explains how ABL kinases phosphorylates poor targets on the same substrate if they are properly positioned and how relatively poor substrate proteins might be recruited to ABL through a complex with strong substrates that can also dock with the SH2 pocket. 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.

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                 ....*....|....*....|....*....|....*....|....*....|.
gi 414073168 581 GFVSRSQERRLLKKTISGTFLLRFSETSEGGITCSwVEHqdDDKVLIYSVQ 631
Cdd:cd09935    8 GPISRNAAEYLLSSGINGSFLVRESESSPGQYSIS-LRY--DGRVYHYRIS 55