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 255759968 573 WFDGVMEVLKKHHKPHWNDGAILGFVNKQQAHDLLINKPDGTFLLRFSDSEIGGITIAWKFDSPDRNLWNLKPFTTRDFS 652
Cdd:cd10421    1 WFDGVMEVLKKHHKPHWNDGAILGFVNKQQAHDLLINKPDGTFLLRFSDSEIGGITIAWKFDSPDRNLWNLKPFTTRDFS 80

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 255759968 653 IRSLADRLGDLNYLIYVFPDRPKDEVFAKYYTPVL----GSSMHPQMPEPAPPTWTRLLP 708
Cdd:cd10421   81 IRSLADRLGDLNYLIYVFPDRPKDEVFSKYYTPVLakavDGYVKPQIKQVVPEFVSASAD 140

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 255759968    4 WIQAQQLQGDALRQMQVLYGQHFPIEVRHYLAQWIESQPWDAIDldnpQDRGQATQLLEGLVQELQKKAEHQVGEDGFLL 83
Cdd:pfam02865   3 WAQLQQLDGEALEQVQQLYGDHFPIEVRHYLAQWIESQDWEDAA----QDESLATVLFHALLSELDSQASRFVQEDNFLL 78

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 255759968   84 KIKLGHYATQLQNTYDRCPMELVRCIRHILYNEQRLVREAN 124
Cdd:pfam02865  79 KHKLREIAKNLQSRYQENPLELARIIRNCLREERRILQEAE 119

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 255759968 573 WFDGVMEVLKKHHKPHWNDGAILGFVNKQQAHDLLINKPDGTFLLRFSDSEIGGITIAWKFDSPDRNLWNLKPFTTRDFS 652
Cdd:cd10421    1 WFDGVMEVLKKHHKPHWNDGAILGFVNKQQAHDLLINKPDGTFLLRFSDSEIGGITIAWKFDSPDRNLWNLKPFTTRDFS 80

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 255759968 653 IRSLADRLGDLNYLIYVFPDRPKDEVFAKYYTPVL----GSSMHPQMPEPAPPTWTRLLP 708
Cdd:cd10421   81 IRSLADRLGDLNYLIYVFPDRPKDEVFSKYYTPVLakavDGYVKPQIKQVVPEFVSASAD 140

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 255759968  336 KQPPQVLKTQTKFAATVRLLVGGKLNVhMNPPQVKATIISEQQAKSLLKNENTR-NECSGEILNNCCVMEYHQATGTLSA 414
Cdd:pfam02864   1 KQPPQVLKTNTKFSVTVRLLVGLPLNI-ELNPQVKVKIVSEKQARELQQIKGFRkFNISGEILNNKALLEYESQNGGLSA 79

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|....*
gi 255759968  415 HFRNMSLKRIKRADRRGAESVTEEKFTVLFESQFSVGsnELVFQVKTLSLPVVVI 469
Cdd:pfam02864  80 EFRNLSLKEIKRGERKGSLSVTEEKFALLFETQFTLG--GLVFDLWTLSLPVVVI 132

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 255759968    4 WIQAQQLQGDALRQMQVLYGQHFPIEVRHYLAQWIESQPWDAIDldnpQDRGQATQLLEGLVQELQKKAEHQVGEDGFLL 83
Cdd:pfam02865   3 WAQLQQLDGEALEQVQQLYGDHFPIEVRHYLAQWIESQDWEDAA----QDESLATVLFHALLSELDSQASRFVQEDNFLL 78

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|.
gi 255759968   84 KIKLGHYATQLQNTYDRCPMELVRCIRHILYNEQRLVREAN 124
Cdd:pfam02865  79 KHKLREIAKNLQSRYQENPLELARIIRNCLREERRILQEAE 119

SH2 domain;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 255759968  589 WNDGAIlgfvNKQQAHDLLIN-KPDGTFLLRFSDSEIGGITIAWKFDspDRNLWNLKPFTTRDFSIRSLADRLGDLNYLI 667
Cdd:pfam00017   1 WYHGKI----SRQEAERLLLNgKPDGTFLVRESESTPGGYTLSVRDD--GKVKHYKIQSTDNGGYYISGGVKFSSLAELV 74

                  .
gi 255759968  668 Y 668
Cdd:pfam00017  75 E 75

exonuclease SbcC; All proteins in this family for which functions are known are part of an exonuclease complex with sbcD homologs. This complex is involved in the initiation of recombination to regulate the levels of palindromic sequences in DNA. This family is based on the phylogenomic analysis of JA Eisen (1999, Ph.D. Thesis, Stanford University). [DNA metabolism, DNA replication, recombination, and repair]

                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 255759968   141 HLQINQRFEELRLITQDTENELKKL---QQTQEYFIIQYQESLRIQAQ-FAQLGQLNP--QERMSRETALQQKQVSLETW 214
Cdd:TIGR00618  193 HGKAELLTLRSQLLTLCTPCMPDTYherKQVLEKELKHLREALQQTQQsHAYLTQKREaqEEQLKKQQLLKQLRARIEEL 272

                           90       100       110       120       130       140       150       160
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 255759968   215 LQREAQ-TLQQYRVELAEK------HQKTLQLLRKQQTII----------LDDELIQWKRRQQLAGNGGPPEGSLDVLQS 277
Cdd:TIGR00618  273 RAQEAVlEETQERINRARKaaplaaHIKAVTQIEQQAQRIhtelqskmrsRAKLLMKRAAHVKQQSSIEEQRRLLQTLHS 352

                          170       180
                   ....*....|....*....|....*.
gi 255759968   278 WCEKLAEiiwQNRQQIRRAEHLCQQL 303
Cdd:TIGR00618  353 QEIHIRD---AHEVATSIREISCQQH 375

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 255759968 573 WFDGVMEVLKKHHKPHWNDGAILGFVNKQQAHDLLINKPDGTFLLRFSDSEIGGITIAWKFDSPDRNLWNLKPFTTRDFS 652
Cdd:cd10421    1 WFDGVMEVLKKHHKPHWNDGAILGFVNKQQAHDLLINKPDGTFLLRFSDSEIGGITIAWKFDSPDRNLWNLKPFTTRDFS 80

                         90       100       110       120       130       140
                 ....*....|....*....|....*....|....*....|....*....|....*....|
gi 255759968 653 IRSLADRLGDLNYLIYVFPDRPKDEVFAKYYTPVL----GSSMHPQMPEPAPPTWTRLLP 708
Cdd:cd10421   81 IRSLADRLGDLNYLIYVFPDRPKDEVFSKYYTPVLakavDGYVKPQIKQVVPEFVSASAD 140

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 255759968 573 WFDGVMEVLKKHHKPHWNDGAILGFVNKQQAHDLLINKPDGTFLLRFSDSEIGGITIAWKFDSPDRNLWNLKPFTTRDFS 652
Cdd:cd10376    1 WFDGVMEVLKKHLKPHWNDGAILGFVNKQQAHDLLINKPDGTFLLRFSDSEIGGITIAWKFDSPDRALWNLMPFTTRDFS 80

                         90       100       110       120       130
                 ....*....|....*....|....*....|....*....|....*....|....
gi 255759968 653 IRSLADRLGDLNYLIYVFPDRPKDEVFAKYYTPVLGSS------MHPQMPEPAP 700
Cdd:cd10376   81 IRSLADRLGDLNYLIYVFPDRPKDEVFSKYYTPVLCNPsavdgyVKPQIKQVVP 134

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 255759968 573 WFDGVMEVLKKHHKPHWNDGAILGFVNKQQAHDLLINKPDGTFLLRFSDSEIGGITIAWKFDSPDRNLWNLKPFTTRDFS 652
Cdd:cd10420    1 WFDGVMEVLKKHLKPHWNDGAILGFVNKQQAHDLLINKPDGTFLLRFSDSEIGGITIAWKFDSQERMFWNLMPFTTRDFS 80

                         90       100       110
                 ....*....|....*....|....*....|....
gi 255759968 653 IRSLADRLGDLNYLIYVFPDRPKDEVFAKYYTPV 686
Cdd:cd10420   81 IRSLADRLGDLNYLIYVFPDRPKDEVYSKYYTPV 114

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 255759968 332 FIIEKQPPQVLKTQTKFAATVRLLVGGK-LNVHMNPPQVKATIISEQQAKSLLKNE--NTRNECSGEILNNCCVMEYHQA 408
Cdd:cd16850    1 FLVEKQPPQVLKTQTKFQAGVRFLLGLRfLGAPAKPPLVRADMVTEKQARELSQPQgpGAGNENTGEIINNTVPLENNIT 80

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 255759968 409 TGTLSAHFRNMSLKRIKRADRRGAESVTEEKFTVLFESQFSVGSNELVFQVKTLSLPVVVIVHGSQDHNATATVLWDNAF 488
Cdd:cd16850   81 SKCCCATFKNLLLKKIKRCERKGSESVTEEKCAVLFSADFTLGPGKLPIQLQALSLPVVVIVHGNQDNNAKATILWDNAF 160

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 255759968 573 WFDGVMEVLKKHHKPHWNDGAILGFVNKQQAHDLLINKPDGTFLLRFSDSEIGGITIAWKFDSPD--RNLWNLKPFTTRD 650
Cdd:cd09919    1 WFFAIMLLTKRHLLKLWQDGLIMGFISKEEAEDLLKKKPPGTFLLRFSDSELGGITIAWVNEDPDgqSQVIHLQPYTKKD 80

                         90       100       110
                 ....*....|....*....|....*....|....*
gi 255759968 651 FSIRSLADRLGDLNYLIYVFPDRPKDEVFAKYYTP 685
Cdd:cd09919   81 LDIRSLADRIRDLPQLVYLYPDIPKDEAFGKYYSP 115

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 255759968     2 AGWIQAQQLQGDALRQMQVLYGQHFPIEVRHYLAQWIESQPWDAIDLDNPqdrgQATQLLEGLVQELQKKAEHQVGEDGF 81
Cdd:smart00964   1 SQWAQLQQLDSKFLEQVQQLYGDNFPMELRHYLADWIESQDWELAANDEA----QATRLFHNLLEQLDQQLSRFSQESNF 76

                           90       100       110       120
                   ....*....|....*....|....*....|....*....|....
gi 255759968    82 LLKIKLGHYATQLQNTYDRCPMELVRCIRHILYNEQRLVREANN 125
Cdd:smart00964  77 LLKHNLRHIKSNLQSLYQENPLELARIIRNILQEERRILAEASR 120

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 255759968 212 ETWLQREaqTLQQYRVELAEKHQKTLQLLRKQQTIILDDELIQWKRRQQLAGNGGPPEGSLDVLQSWCEKLAEIIWQNRQ 291
Cdd:cd14786   16 ILWEELK--SLQQKRKEVLVKLLRRLLMAEEIQQELIIEELKNWKRRQQLAGNGAPREQSLDELQNWFESLAEFLWQLRQ 93

                         90       100       110
                 ....*....|....*....|....*....|....*..
gi 255759968 292 QIRRAEHLCqqlpiPGPVEEMLAEVNATITDIISALV 328
Cdd:cd14786   94 QVKKLLELF-----GDPIDPQLNDLLERVQELQKNLV 125

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 255759968 563 LPGWNYTFWQWFDGVMEVLKKHHKPHWNDGAILGFVNKQQAHDLLINKPDGTFLLRFSD-SEIGGITIAW--KFDSPDRN 639
Cdd:cd10374    1 MAGKGFSFWVWLDNIIDLVKKYILALWNEGYIMGFISKERERAILSTKPPGTFLLRFSEsSKEGGVTFTWveKDISGKTQ 80

                         90       100       110       120       130       140       150
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 255759968 640 LWNLKPFTTRDFSIRSLAD-----RLGD-----LNYLIYVFPDRPKDEVFAKYYTPvlgSSMHPQMPEPA 699
Cdd:cd10374   81 IQSVEPYTKQQLNNMSFAEiimgyKIMDatnilVSPLVYLYPDIPKEEAFGKYCRP---ESQEHPEADPG 147

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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 255759968 139 QKHLQINQRFEELRLITQDTENELKKLQQTQEYFIIQYQeslRIQAQfAQLGQLNPqermSRETALQQKQVSLETWLQRE 218
Cdd:cd16853    1 EKQQMLEQHLQDVRKRVQDLEQKMKVVENLQDDFDFNYK---TLKSQ-GDMQDLNG----NNQSVTRQKMQQLEQMLTAL 72

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 255759968 219 AQTLQQYRVELAekhqKTLQLLRKQQTIILDDELIQWKRRQQLAGNGGPPEGSLDVLQSWCEKLAEIIWQNRQQIRRAEH 298
Cdd:cd16853   73 DQMRRQIVSELA----GLLSAMEYVQKNLTDEELADWKRRQQIACIGGPPNICLDRLENWITSLAESQLQTRQQIKKLEE 148

                 ....*....
gi 255759968 299 LCQQLPIPG 307
Cdd:cd16853  149 LQQKVSYKG 157

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 255759968 332 FIIEKQP--------PQVLKTQTKFAATVRLLVG-GKLNVHMnppQVKATIiseqqaksllkNENTRNECSGEilNNCCV 402
Cdd:cd16848    1 FVVERQPcmpthpqrPMVLKTLIQFTVKLRLLIKlPELNYQI---RVKATI-----------DNNRRFVLCGT--HVKAM 64

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 255759968 403 MEYHQATGTLSAHFRNMSLKRIK----RADRRGAESVTEEKFTVLFESQFSVGSneLVFQVKTLSLPVVVIVHGSQDHNA 478
Cdd:cd16848   65 NLEESVNGSLSVEFRHLQPKEMKpsggSKGNEGPHMVTEELHSISFETQFSLYG--LTIDLETSSLPVVMISNVSQLPNA 142

                 ....*...
gi 255759968 479 TATVLWDN 486
Cdd:cd16848  143 WASIIWYN 150

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 255759968 140 KHLQINQRFEELRLITQDTENELKKLQQTQ-EY-FIIQYQESlriqaqfaqlgqlnpqeRMSRETALQQKQVSLETW-LQ 216
Cdd:cd16851    1 KQKELDAKVKDLKNSVQDAEQDIKSLEDLQdEYdFKRKTLQS-----------------REEETNGVAKEELKKEKLkLR 63

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 255759968 217 REAQTLQQYRVELAEKHQKTLQLLRKQQTIILDDELIQWKRRQQLAGNGGPPEGSLDVLQSWCEKLAEIIWQNRQQIRRA 296
Cdd:cd16851   64 KMFIKLKDKRKEVVHKIIELLNVTELTQFALINDELVEWKRRQQMACIGGPPNACLDQLQNWFTIVAESLQQVRQQLKKL 143

                 ....*..
gi 255759968 297 EHLCQQL 303
Cdd:cd16851  144 QELEQKL 150

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 255759968 141 HLQINQRFEELRLITQDTENELKKLQQTQEYFIIQYQEslriqaqfaqlgqlnpQERMSReTALQQKQVSLETWLQREAQ 220
Cdd:cd16852    2 QHEIEKRINDLKTRIQCLEHSIRQLEDLQDTFDFKYKT----------------HTMDKS-TSPDDKQTKQQQILQGMLN 64

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 255759968 221 TLQQYRVELAEKhQKTLQLLRKQQTIILDDELIQWKRRQQLAGNGGPPEGSLDVLQSWCEKLAEIIWQNRQQIRRAEHLC 300
Cdd:cd16852   65 ELDRFRKEVLSK-MKVLLGRRDTLRELLLEELVEWKRRQQKACIGAPDDTSLEQLEKWFTKVAECLFQLRKFLKKLEELM 143

                        170       180
                 ....*....|....*....|....*....
gi 255759968 301 QQL-----PIPGPVEEMLAEVNATITDII 324
Cdd:cd16852  144 GKVsyehdPLKKQKPLLQQRVDELLTSLL 172

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

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 255759968 173 IIQYQESLRIQAQFAQLGQLNPQERMSRETALQQKQVSLETWLQREAQTLQQYRVELAekhQKTLQLLRKQQTIILDDEL 252
Cdd:cd16856   17 IHQLQEELKFDVENLELQHRVGQIHRLQLSLQQEKKSERIQQQEANGTSPLQERAQLL---QEAVGELEQAQSQVLKRIQ 93

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 255759968 253 IqWKRRQQLAGNGGPPEGSLDVLQSWCEKLAEIIWQNRQQIRRAEHLCQQLPIPGpVEEMLAEVnatitdiISALVTSTF 332
Cdd:cd16856   94 I-WKRQQQLAGNGAPFDENLSPLQTRCEQLVDVNFQLRQEVMLAGGELGSELLST-LQERLNSL-------LQTLIQSSL 164

                 ...
gi 255759968 333 IIE 335
Cdd:cd16856  165 VVE 167

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 255759968 332 FIIEKQP--------PQVLKTQTKFAATVRLLVG-GKLNVHMnppQVKATIISEQQAKSLLKNENTRNecsgeIL-NNCC 401
Cdd:cd16847    1 FVVERQPcmpmhpdrPLVIKTGVQFTTKVRLLVKfPELNYQL---KIKVCIDKDSGDVAALRGSRKFN-----ILgTNTK 72

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 255759968 402 VMEYHQAT-GTLSAHFRNMSLKRIK-----RADRRGAESVTEEKFTVLFESQfsVGSNELVFQVKTLSLPVVVIVHGSQD 475
Cdd:cd16847   73 VMNMEESNnGSLSAEFKHLTLREQRcgnggRANCDASLIVTEELHLITFETE--VYHQGLKIDLETHSLPVVVISNICQM 150

                        170
                 ....*....|.
gi 255759968 476 HNATATVLWDN 486
Cdd:cd16847  151 PNAWASILWYN 161

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.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|
gi 255759968 596 GFVNKQQAHDLLINKPDGTFLLRFSDSEIGGITIAWKFDS 635
Cdd:cd00173    5 GSISREEAERLLRGKPDGTFLVRESSSEPGDYVLSVRSGD 44

Caldesmon;

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 255759968  142 LQINQRFEELRLITQDTEN-ELKKLQQTQEYFIIQYQESLRIQAQFAQLGQlnpQERMSRETALQQKQVSLETWLQREAQ 220
Cdd:pfam02029 244 LEAEQKLEELRRRRQEKESeEFEKLRQKQQEAELELEELKKKREERRKLLE---EEEQRRKQEEAERKLREEEEKRRMKE 320

                          90
                  ....*....|....*
gi 255759968  221 TLQQYRVELAEKHQK 235
Cdd:pfam02029 321 EIERRRAEAAEKRQK 335

Src homology 2 (SH2) domain found in the Vav family; Vav proteins are involved in several processes that require cytoskeletal reorganization, such as the formation of the immunological synapse (IS), phagocytosis, platelet aggregation, spreading, and transformation. Vavs function as guanine nucleotide exchange factors (GEFs) for the Rho/Rac family of GTPases. Vav family members have several conserved motifs/domains including: a leucine-rich region, a leucine-zipper, a calponin homology (CH) domain, an acidic domain, a Dbl-homology (DH) domain, a pleckstrin homology (PH) domain, a cysteine-rich domain, 2 SH3 domains, a proline-rich region, and a SH2 domain. Vavs are the only known Rho GEFs that have both the DH/PH motifs and SH2/SH3 domains in the same protein. The leucine-rich helix-loop-helix (HLH) domain is thought to be involved in protein heterodimerization with other HLH proteins and it may function as a negative regulator by forming inactive heterodimers. The CH domain is usually involved in the association with filamentous actin, but in Vav it controls NFAT stimulation, Ca2+ mobilization, and its transforming activity. Acidic domains are involved in protein-protein interactions and contain regulatory tyrosines. The DH domain is a GDP-GTP exchange factor on Rho/Rac GTPases. The PH domain in involved in interactions with GTP-binding proteins, lipids and/or phosphorylated serine/threonine residues. The SH3 domain is involved in localization of proteins to specific sites within the cell interacting with protein with proline-rich sequences. The SH2 domain mediates a high affinity interaction with tyrosine phosphorylated proteins. There are three Vav mammalian family members: Vav1 which is expressed in the hematopoietic system, Vav2 and Vav3 are more ubiquitously expressed. The members here include insect and amphibian Vavs. 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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 255759968 568 YTFWQWFDGVMEvlkkhhkphwndgailgfvnKQQAHDLLINKPDGTFLLRFSDSEIGGITIAWKFD 634
Cdd:cd09940    2 LSEFLWFVGEME--------------------RDTAENRLENRPDGTYLVRVRPQGETQYALSIKYN 48

Domain of unknown function (DUF4670); This family of proteins is found in eukaryotes. Proteins in this family are typically between 373 and 763 amino acids in length.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 255759968  139 QKHLQINQ--RFEELRLITQDTENElkklQQTQEyfiiqyqESLRIQAQfaqlgqlnpQERMSRETALQQKQVSLETW-- 214
Cdd:pfam15709 375 REELELEQqrRFEEIRLRKQRLEEE----RQRQE-------EEERKQRL---------QLQAAQERARQQQEEFRRKLqe 434

                          90       100       110       120       130
                  ....*....|....*....|....*....|....*....|....*....|..
gi 255759968  215 LQREAQTLQQYRVELAEKHQKTL--QLLRKQQTI--ILDDELIQWKRRQQLA 262
Cdd:pfam15709 435 LQRKKQQEEAERAEAEKQRQKELemQLAEEQKRLmeMAEEERLEYQRQKQEA 486