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Conserved domains on  [gi|21618338|ref|NP_003141|]
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signal transducer and activator of transcription 3 isoform 2 [Homo sapiens]

Protein Classification

SH2 domain-containing protein; tyrosine-protein kinase( domain architecture ID 13929435)

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

Graphical summary

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List of domain hits

Name Accession Description Interval E-value
STAT3_CCD cd16853
Coiled-coil domain of Signal Transducer and Activator of Transcription 3 (STAT3); This family ...
139-318 1.31e-126

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


:

Pssm-ID: 341078 [Multi-domain]  Cd Length: 180  Bit Score: 375.10  E-value: 1.31e-126
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 139 EKQQMLEQHLQDVRKRVQDLEQKMKVVENLQDDFDFNYKTLKSQGDMQDLNGNNQSVTRQKMQQLEQMLTALDQMRRSIV 218
Cdd:cd16853   1 EKQQMLEQHLQDVRKRVQDLEQKMKVVENLQDDFDFNYKTLKSQGDMQDLNGNNQSVTRQKMQQLEQMLTALDQMRRQIV 80
                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 219 SELAGLLSAMEYVQKTLTDEELADWKRRQQIACIGGPPNICLDRLENWITSLAESQLQTRQQIKKLEELQQKVSYKGDPI 298
Cdd:cd16853  81 SELAGLLSAMEYVQKNLTDEELADWKRRQQIACIGGPPNICLDRLENWITSLAESQLQTRQQIKKLEELQQKVSYKGDPI 160
                       170       180
                ....*....|....*....|
gi 21618338 299 VQHRPMLEERIVELFRNLMK 318
Cdd:cd16853 161 VQHRPMLEERIVELFRNLMK 180
SH2_STAT3 cd10374
Src homology 2 (SH2) domain found in signal transducer and activator of transcription (STAT) 3 ...
554-714 1.26e-121

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


:

Pssm-ID: 198237  Cd Length: 162  Bit Score: 361.66  E-value: 1.26e-121
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 554 MAGKGFSFWVWLDNIIDLVKKYILALWNEGYIMGFISKERERAILSTKPPGTFLLRFSESSKEGGVTFTWVEKDISGKTQ 633
Cdd:cd10374   1 MAGKGFSFWVWLDNIIDLVKKYILALWNEGYIMGFISKERERAILSTKPPGTFLLRFSESSKEGGVTFTWVEKDISGKTQ 80
                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 634 IQSVEPYTKQQLNNMSFAEIIMGYKIMDATNILVSPLVYLYPDIPKEEAFGKYCRPESQEHPEADPG-AAPYLKTKFICV 712
Cdd:cd10374  81 IQSVEPYTKQQLNNMSFAEIIMGYKIMDATNILVSPLVYLYPDIPKEEAFGKYCRPESQEHPEADPGsAAPYLKTKFICV 160

                ..
gi 21618338 713 TP 714
Cdd:cd10374 161 TP 162
STAT3_DBD cd16847
DNA-binding domain of Signal Transducer and Activator of Transcription 3 (STAT3); This family ...
321-484 1.95e-114

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


:

Pssm-ID: 341085  Cd Length: 164  Bit Score: 343.23  E-value: 1.95e-114
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 321 FVVERQPCMPMHPDRPLVIKTGVQFTTKVRLLVKFPELNYQLKIKVCIDKDSGDVAALRGSRKFNILGTNTKVMNMEESN 400
Cdd:cd16847   1 FVVERQPCMPMHPDRPLVIKTGVQFTTKVRLLVKFPELNYQLKIKVCIDKDSGDVAALRGSRKFNILGTNTKVMNMEESN 80
                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 401 NGSLSAEFKHLTLREQRCGNGGRANCDASLIVTEELHLITFETEVYHQGLKIDLETHSLPVVVISNICQMPNAWASILWY 480
Cdd:cd16847  81 NGSLSAEFKHLTLREQRCGNGGRANCDASLIVTEELHLITFETEVYHQGLKIDLETHSLPVVVISNICQMPNAWASILWY 160

                ....
gi 21618338 481 NMLT 484
Cdd:cd16847 161 NMLT 164
STAT_int smart00964
STAT protein, protein interaction domain; STAT proteins (Signal Transducers and Activators of ...
2-120 1.13e-54

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


:

Pssm-ID: 214942  Cd Length: 120  Bit Score: 183.65  E-value: 1.13e-54
                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338      2 AQWNQLQQLDTRYLEQLHQLYSDSFPMELRQFLAPWIESQDWAYAASKESHATLVFHNLLGEIDQQYSRFLQESNVLYQH 81
Cdd:smart00964   1 SQWAQLQQLDSKFLEQVQQLYGDNFPMELRHYLADWIESQDWELAANDEAQATRLFHNLLEQLDQQLSRFSQESNFLLKH 80
                           90       100       110
                   ....*....|....*....|....*....|....*....
gi 21618338     82 NLRRIKQFLQSRYLEKPMEIARIVARCLWEESRLLQTAA 120
Cdd:smart00964  81 NLRHIKSNLQSLYQENPLELARIIRNILQEERRILAEAS 119
 
Name Accession Description Interval E-value
STAT3_CCD cd16853
Coiled-coil domain of Signal Transducer and Activator of Transcription 3 (STAT3); This family ...
139-318 1.31e-126

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


Pssm-ID: 341078 [Multi-domain]  Cd Length: 180  Bit Score: 375.10  E-value: 1.31e-126
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 139 EKQQMLEQHLQDVRKRVQDLEQKMKVVENLQDDFDFNYKTLKSQGDMQDLNGNNQSVTRQKMQQLEQMLTALDQMRRSIV 218
Cdd:cd16853   1 EKQQMLEQHLQDVRKRVQDLEQKMKVVENLQDDFDFNYKTLKSQGDMQDLNGNNQSVTRQKMQQLEQMLTALDQMRRQIV 80
                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 219 SELAGLLSAMEYVQKTLTDEELADWKRRQQIACIGGPPNICLDRLENWITSLAESQLQTRQQIKKLEELQQKVSYKGDPI 298
Cdd:cd16853  81 SELAGLLSAMEYVQKNLTDEELADWKRRQQIACIGGPPNICLDRLENWITSLAESQLQTRQQIKKLEELQQKVSYKGDPI 160
                       170       180
                ....*....|....*....|
gi 21618338 299 VQHRPMLEERIVELFRNLMK 318
Cdd:cd16853 161 VQHRPMLEERIVELFRNLMK 180
SH2_STAT3 cd10374
Src homology 2 (SH2) domain found in signal transducer and activator of transcription (STAT) 3 ...
554-714 1.26e-121

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


Pssm-ID: 198237  Cd Length: 162  Bit Score: 361.66  E-value: 1.26e-121
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 554 MAGKGFSFWVWLDNIIDLVKKYILALWNEGYIMGFISKERERAILSTKPPGTFLLRFSESSKEGGVTFTWVEKDISGKTQ 633
Cdd:cd10374   1 MAGKGFSFWVWLDNIIDLVKKYILALWNEGYIMGFISKERERAILSTKPPGTFLLRFSESSKEGGVTFTWVEKDISGKTQ 80
                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 634 IQSVEPYTKQQLNNMSFAEIIMGYKIMDATNILVSPLVYLYPDIPKEEAFGKYCRPESQEHPEADPG-AAPYLKTKFICV 712
Cdd:cd10374  81 IQSVEPYTKQQLNNMSFAEIIMGYKIMDATNILVSPLVYLYPDIPKEEAFGKYCRPESQEHPEADPGsAAPYLKTKFICV 160

                ..
gi 21618338 713 TP 714
Cdd:cd10374 161 TP 162
STAT3_DBD cd16847
DNA-binding domain of Signal Transducer and Activator of Transcription 3 (STAT3); This family ...
321-484 1.95e-114

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


Pssm-ID: 341085  Cd Length: 164  Bit Score: 343.23  E-value: 1.95e-114
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 321 FVVERQPCMPMHPDRPLVIKTGVQFTTKVRLLVKFPELNYQLKIKVCIDKDSGDVAALRGSRKFNILGTNTKVMNMEESN 400
Cdd:cd16847   1 FVVERQPCMPMHPDRPLVIKTGVQFTTKVRLLVKFPELNYQLKIKVCIDKDSGDVAALRGSRKFNILGTNTKVMNMEESN 80
                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 401 NGSLSAEFKHLTLREQRCGNGGRANCDASLIVTEELHLITFETEVYHQGLKIDLETHSLPVVVISNICQMPNAWASILWY 480
Cdd:cd16847  81 NGSLSAEFKHLTLREQRCGNGGRANCDASLIVTEELHLITFETEVYHQGLKIDLETHSLPVVVISNICQMPNAWASILWY 160

                ....
gi 21618338 481 NMLT 484
Cdd:cd16847 161 NMLT 164
STAT_alpha pfam01017
STAT protein, all-alpha domain; STAT proteins (Signal Transducers and Activators of ...
145-313 3.30e-68

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


Pssm-ID: 460026  Cd Length: 167  Bit Score: 222.10  E-value: 3.30e-68
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338   145 EQHLQDVRKRVQDLEQKMKVVENLQDDFDFNYKTLKSQGdmQDLNGNNQSVTRQKMQQLEQMLTALDQMRRSIVSELAGL 224
Cdd:pfam01017   1 EQRLEELRNRVQETEQDIKQLEDLQDEFDFKYKTLQKLQ--QERTESEDKELKQQKELLQQMLNALDQKRKEVLDKLKEL 78
                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338   225 LSAMEYVQKTLTDEELADWKRRQQIACIGGPPNICLDRLENWITSLAESQLQTRQQIKKLEELQQKVSYKGDPIVQHRPM 304
Cdd:pfam01017  79 LNLLETLQELLLDEELIEWKRRQQLACIGAPPNACLDQLQNWFTALAESLWQLRQQLKKLEELRQKLTYEGDPLTDGLPQ 158

                  ....*....
gi 21618338   305 LEERIVELF 313
Cdd:pfam01017 159 LNERVTELL 167
STAT_int smart00964
STAT protein, protein interaction domain; STAT proteins (Signal Transducers and Activators of ...
2-120 1.13e-54

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


Pssm-ID: 214942  Cd Length: 120  Bit Score: 183.65  E-value: 1.13e-54
                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338      2 AQWNQLQQLDTRYLEQLHQLYSDSFPMELRQFLAPWIESQDWAYAASKESHATLVFHNLLGEIDQQYSRFLQESNVLYQH 81
Cdd:smart00964   1 SQWAQLQQLDSKFLEQVQQLYGDNFPMELRHYLADWIESQDWELAANDEAQATRLFHNLLEQLDQQLSRFSQESNFLLKH 80
                           90       100       110
                   ....*....|....*....|....*....|....*....
gi 21618338     82 NLRRIKQFLQSRYLEKPMEIARIVARCLWEESRLLQTAA 120
Cdd:smart00964  81 NLRHIKSNLQSLYQENPLELARIIRNILQEERRILAEAS 119
STAT_int pfam02865
STAT protein, protein interaction domain; STAT proteins (Signal Transducers and Activators of ...
2-119 3.37e-53

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


Pssm-ID: 460728  Cd Length: 119  Bit Score: 179.72  E-value: 3.37e-53
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338     2 AQWNQLQQLDTRYLEQLHQLYSDSFPMELRQFLAPWIESQDWAYAASKESHATLVFHNLLGEIDQQYSRFLQESNVLYQH 81
Cdd:pfam02865   1 SLWAQLQQLDGEALEQVQQLYGDHFPIEVRHYLAQWIESQDWEDAAQDESLATVLFHALLSELDSQASRFVQEDNFLLKH 80
                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 21618338    82 NLRRIKQFLQSRYLEKPMEIARIVARCLWEESRLLQTA 119
Cdd:pfam02865  81 KLREIAKNLQSRYQENPLELARIIRNCLREERRILQEA 118
STAT_bind pfam02864
STAT protein, DNA binding domain; STAT proteins (Signal Transducers and Activators of ...
325-464 5.45e-52

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


Pssm-ID: 460727  Cd Length: 132  Bit Score: 177.01  E-value: 5.45e-52
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338   325 RQPcmpmhpdrPLVIKTGVQFTTKVRLLVKFP---ELNYQLKIKVCIDKDSGDVAALRGSRKFNILG--TNTKVMNMEES 399
Cdd:pfam02864   1 KQP--------PQVLKTNTKFSVTVRLLVGLPlniELNPQVKVKIVSEKQARELQQIKGFRKFNISGeiLNNKALLEYES 72
                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 21618338   400 NNGSLSAEFKHLTLREQRCGNGgrancDASLIVTEELHLITFETEVYHQGLKIDLETHSLPVVVI 464
Cdd:pfam02864  73 QNGGLSAEFRNLSLKEIKRGER-----KGSLSVTEEKFALLFETQFTLGGLVFDLWTLSLPVVVI 132
SH2 pfam00017
SH2 domain;
584-674 5.71e-13

SH2 domain;


Pssm-ID: 425423 [Multi-domain]  Cd Length: 77  Bit Score: 64.54  E-value: 5.71e-13
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338   584 YIMGFISK-ERERAILSTKPPGTFLLRFSESSKeGGVTFTWVEKDisgktqiqSVEPYTKQQLNNmsfaeiiMGYKIMDA 662
Cdd:pfam00017   1 WYHGKISRqEAERLLLNGKPDGTFLVRESESTP-GGYTLSVRDDG--------KVKHYKIQSTDN-------GGYYISGG 64
                          90
                  ....*....|...
gi 21618338   663 -TNILVSPLVYLY 674
Cdd:pfam00017  65 vKFSSLAELVEHY 77
SH2 smart00252
Src homology 2 domains; Src homology 2 domains bind phosphotyrosine-containing polypeptides ...
586-639 1.94e-04

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


Pssm-ID: 214585 [Multi-domain]  Cd Length: 84  Bit Score: 40.68  E-value: 1.94e-04
                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....
gi 21618338    586 MGFISKERERAILSTKPPGTFLLRFSESSKeGGVTFTWVEKDISGKTQIQSVEP 639
Cdd:smart00252   5 HGFISREEAEKLLKNEGDGDFLVRDSESSP-GDYVLSVRVKGKVKHYRIRRNED 57
 
Name Accession Description Interval E-value
STAT3_CCD cd16853
Coiled-coil domain of Signal Transducer and Activator of Transcription 3 (STAT3); This family ...
139-318 1.31e-126

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


Pssm-ID: 341078 [Multi-domain]  Cd Length: 180  Bit Score: 375.10  E-value: 1.31e-126
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 139 EKQQMLEQHLQDVRKRVQDLEQKMKVVENLQDDFDFNYKTLKSQGDMQDLNGNNQSVTRQKMQQLEQMLTALDQMRRSIV 218
Cdd:cd16853   1 EKQQMLEQHLQDVRKRVQDLEQKMKVVENLQDDFDFNYKTLKSQGDMQDLNGNNQSVTRQKMQQLEQMLTALDQMRRQIV 80
                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 219 SELAGLLSAMEYVQKTLTDEELADWKRRQQIACIGGPPNICLDRLENWITSLAESQLQTRQQIKKLEELQQKVSYKGDPI 298
Cdd:cd16853  81 SELAGLLSAMEYVQKNLTDEELADWKRRQQIACIGGPPNICLDRLENWITSLAESQLQTRQQIKKLEELQQKVSYKGDPI 160
                       170       180
                ....*....|....*....|
gi 21618338 299 VQHRPMLEERIVELFRNLMK 318
Cdd:cd16853 161 VQHRPMLEERIVELFRNLMK 180
SH2_STAT3 cd10374
Src homology 2 (SH2) domain found in signal transducer and activator of transcription (STAT) 3 ...
554-714 1.26e-121

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


Pssm-ID: 198237  Cd Length: 162  Bit Score: 361.66  E-value: 1.26e-121
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 554 MAGKGFSFWVWLDNIIDLVKKYILALWNEGYIMGFISKERERAILSTKPPGTFLLRFSESSKEGGVTFTWVEKDISGKTQ 633
Cdd:cd10374   1 MAGKGFSFWVWLDNIIDLVKKYILALWNEGYIMGFISKERERAILSTKPPGTFLLRFSESSKEGGVTFTWVEKDISGKTQ 80
                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 634 IQSVEPYTKQQLNNMSFAEIIMGYKIMDATNILVSPLVYLYPDIPKEEAFGKYCRPESQEHPEADPG-AAPYLKTKFICV 712
Cdd:cd10374  81 IQSVEPYTKQQLNNMSFAEIIMGYKIMDATNILVSPLVYLYPDIPKEEAFGKYCRPESQEHPEADPGsAAPYLKTKFICV 160

                ..
gi 21618338 713 TP 714
Cdd:cd10374 161 TP 162
STAT3_DBD cd16847
DNA-binding domain of Signal Transducer and Activator of Transcription 3 (STAT3); This family ...
321-484 1.95e-114

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


Pssm-ID: 341085  Cd Length: 164  Bit Score: 343.23  E-value: 1.95e-114
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 321 FVVERQPCMPMHPDRPLVIKTGVQFTTKVRLLVKFPELNYQLKIKVCIDKDSGDVAALRGSRKFNILGTNTKVMNMEESN 400
Cdd:cd16847   1 FVVERQPCMPMHPDRPLVIKTGVQFTTKVRLLVKFPELNYQLKIKVCIDKDSGDVAALRGSRKFNILGTNTKVMNMEESN 80
                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 401 NGSLSAEFKHLTLREQRCGNGGRANCDASLIVTEELHLITFETEVYHQGLKIDLETHSLPVVVISNICQMPNAWASILWY 480
Cdd:cd16847  81 NGSLSAEFKHLTLREQRCGNGGRANCDASLIVTEELHLITFETEVYHQGLKIDLETHSLPVVVISNICQMPNAWASILWY 160

                ....
gi 21618338 481 NMLT 484
Cdd:cd16847 161 NMLT 164
STAT1_DBD cd16845
DNA-binding domain of Signal Transducer and Activator of Transcription 1 (STAT1); This family ...
321-483 6.75e-80

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


Pssm-ID: 341083  Cd Length: 161  Bit Score: 252.87  E-value: 6.75e-80
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 321 FVVERQPCMPMHPDRPLVIKTGVQFTTKVRLLVKFPELNYQLKIKVCIDKDSGDVAALRGSRKFNILGTNTKVMNMEESN 400
Cdd:cd16845   1 FVVERQPCMPTHPQRPLVLKTGVQFTVKLRLLVKLQELNYQLKVKVLFDKDVTEKNTVKGFRKFNILGTNTKVMNMEEST 80
                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 401 NGSLSAEFKHLTLREQRCgNGGRANcDASLIVTEELHLITFETEVYHQGLKIDLETHSLPVVVISNICQMPNAWASILWY 480
Cdd:cd16845  81 NGSLAAEFRHLQLKEQKN-AGTRTN-EGPLIVTEELHSLSFETQLCQPGLVIDLETTSLPIVVISNVSQLPSGWASILWY 158

                ...
gi 21618338 481 NML 483
Cdd:cd16845 159 NML 161
STAT2_DBD cd16846
DNA-binding domain of Signal Transducer and Activator of Transcription 2 (STAT2); This family ...
321-483 3.15e-75

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


Pssm-ID: 341084  Cd Length: 160  Bit Score: 240.49  E-value: 3.15e-75
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 321 FVVERQPCMPMHPDRPLVIKTGVQFTTKVRLLVKFPELNYQLKIKVCIDKDsgdVAALRGSRKFNILGTNTKVMNMEESN 400
Cdd:cd16846   1 FVVETQPCMPQPPRRPLVLKTNTQFSVRVRLLVKLPELNHSLKVEVSVDKN---PPNSKGFRRFNILGTNNKTLNMDEGQ 77
                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 401 NGSLSAEFKHLTLREQRCGNGGRANCDASLIVTEELHLITFETEVYHQGLKIDLETHSLPVVVISNICQMPNAWASILWY 480
Cdd:cd16846  78 SGGLVADFRHLTLKEQKVGGGGKGSNEGSLSVTEELHLITFTTDYKYQGLKVKLETSTLPVVVISNMSQLSSAWASVLWF 157

                ...
gi 21618338 481 NML 483
Cdd:cd16846 158 NLL 160
STAT4_DBD cd16848
DNA-binding domain of Signal Transducer and Activator of Transcription 4 (STAT4); This family ...
321-483 3.73e-74

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


Pssm-ID: 341086  Cd Length: 152  Bit Score: 237.61  E-value: 3.73e-74
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 321 FVVERQPCMPMHPDRPLVIKTGVQFTTKVRLLVKFPELNYQLKIKVCIDKDsgdvaalrgsRKFNILGTNTKVMNMEESN 400
Cdd:cd16848   1 FVVERQPCMPTHPQRPMVLKTLIQFTVKLRLLIKLPELNYQIRVKATIDNN----------RRFVLCGTHVKAMNLEESV 70
                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 401 NGSLSAEFKHLTLREQRCGNGGRANcDASLIVTEELHLITFETEVYHQGLKIDLETHSLPVVVISNICQMPNAWASILWY 480
Cdd:cd16848  71 NGSLSVEFRHLQPKEMKPSGGSKGN-EGPHMVTEELHSISFETQFSLYGLTIDLETSSLPVVMISNVSQLPNAWASIIWY 149

                ...
gi 21618338 481 NML 483
Cdd:cd16848 150 NLL 152
STAT_alpha pfam01017
STAT protein, all-alpha domain; STAT proteins (Signal Transducers and Activators of ...
145-313 3.30e-68

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


Pssm-ID: 460026  Cd Length: 167  Bit Score: 222.10  E-value: 3.30e-68
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338   145 EQHLQDVRKRVQDLEQKMKVVENLQDDFDFNYKTLKSQGdmQDLNGNNQSVTRQKMQQLEQMLTALDQMRRSIVSELAGL 224
Cdd:pfam01017   1 EQRLEELRNRVQETEQDIKQLEDLQDEFDFKYKTLQKLQ--QERTESEDKELKQQKELLQQMLNALDQKRKEVLDKLKEL 78
                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338   225 LSAMEYVQKTLTDEELADWKRRQQIACIGGPPNICLDRLENWITSLAESQLQTRQQIKKLEELQQKVSYKGDPIVQHRPM 304
Cdd:pfam01017  79 LNLLETLQELLLDEELIEWKRRQQLACIGAPPNACLDQLQNWFTALAESLWQLRQQLKKLEELRQKLTYEGDPLTDGLPQ 158

                  ....*....
gi 21618338   305 LEERIVELF 313
Cdd:pfam01017 159 LNERVTELL 167
STAT1_CCD cd16851
Coiled-coil domain of Signal Transducer and Activator of Transcription 1 (STAT1); This family ...
140-317 4.48e-57

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


Pssm-ID: 341076  Cd Length: 176  Bit Score: 192.69  E-value: 4.48e-57
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 140 KQQMLEQHLQDVRKRVQDLEQKMKVVENLQDDFDFNYKTLKSqgDMQDLNGNNQSVTRQKMQQLEQMLTALDQMRRSIVS 219
Cdd:cd16851   1 KQKELDAKVKDLKNSVQDAEQDIKSLEDLQDEYDFKRKTLQS--REEETNGVAKEELKKEKLKLRKMFIKLKDKRKEVVH 78
                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 220 ELAGLLSAMEYVQKTLTDEELADWKRRQQIACIGGPPNICLDRLENWITSLAESQLQTRQQIKKLEELQQKVSYKGDPIV 299
Cdd:cd16851  79 KIIELLNVTELTQFALINDELVEWKRRQQMACIGGPPNACLDQLQNWFTIVAESLQQVRQQLKKLQELEQKLTYENDPIT 158
                       170
                ....*....|....*...
gi 21618338 300 QHRPMLEERIVELFRNLM 317
Cdd:cd16851 159 KNKQALEERALSLFKNLI 176
STAT_DBD cd14801
DNA-binding domain of Signal Transducer and Activator of Transcription (STAT); This family ...
321-483 8.86e-57

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


Pssm-ID: 341082  Cd Length: 157  Bit Score: 190.99  E-value: 8.86e-57
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 321 FVVERQPcmpmhpdrPLVIKTGVQFTTKVRLLVKFPE--LNYQLKIKVCIDKDS-----GDVAALRGSRKFNILGTNTKV 393
Cdd:cd14801   1 FVVEKQP--------PQVLKTGTKFTATVRLLVGDKLgiHLNLPKVKASIISEEqakslVENKTLGGFRSGEILGNNTKV 72
                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 394 MNMEESNNGsLSAEFKHLTLREQRCGNGGRAncdaSLIVTEELHLITFETEVYHQGLKIDLETHSLPVVVISNICQMPNA 473
Cdd:cd14801  73 MEYEESTGG-LSAEFKNLSLKKIKRGDRKSG----DESVTEEKFALLFTTQFTIGGLTIDLWTLSLPVVVIVHGNQEPSA 147
                       170
                ....*....|
gi 21618338 474 WASILWYNML 483
Cdd:cd14801 148 WATILWDNAF 157
SH2_STAT1 cd10372
Src homology 2 (SH2) domain found in signal transducer and activator of transcription (STAT) 1 ...
564-710 2.82e-56

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


Pssm-ID: 198235  Cd Length: 151  Bit Score: 189.35  E-value: 2.82e-56
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 564 WLDNIIDLVKKYILALWNEGYIMGFISKERERAILSTKPPGTFLLRFSESSKEGGVTFTWVEKDISGKT-QIQSVEPYTK 642
Cdd:cd10372   1 WIESILELIKKHLLSLWNDGCIMGFISKERERALLKDQQPGTFLLRFSESSREGAITFTWVERSQNGGEpDFHAVEPYTK 80
                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|.
gi 21618338 643 QQLNNMSFAEIIMGYKIMDATNILVSPLVYLYPDIPKEEAFGK-YCRP-ESQEHPEAD-PGAAPYLKTKFI 710
Cdd:cd10372  81 KELSAVTFPDIIRNYKVMAAENIPENPLKYLYPNIDKDHAFGKyYSRPkEAPEPMELDgPKGTGYIKTELI 151
STAT_int smart00964
STAT protein, protein interaction domain; STAT proteins (Signal Transducers and Activators of ...
2-120 1.13e-54

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


Pssm-ID: 214942  Cd Length: 120  Bit Score: 183.65  E-value: 1.13e-54
                           10        20        30        40        50        60        70        80
                   ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338      2 AQWNQLQQLDTRYLEQLHQLYSDSFPMELRQFLAPWIESQDWAYAASKESHATLVFHNLLGEIDQQYSRFLQESNVLYQH 81
Cdd:smart00964   1 SQWAQLQQLDSKFLEQVQQLYGDNFPMELRHYLADWIESQDWELAANDEAQATRLFHNLLEQLDQQLSRFSQESNFLLKH 80
                           90       100       110
                   ....*....|....*....|....*....|....*....
gi 21618338     82 NLRRIKQFLQSRYLEKPMEIARIVARCLWEESRLLQTAA 120
Cdd:smart00964  81 NLRHIKSNLQSLYQENPLELARIIRNILQEERRILAEAS 119
STAT_int pfam02865
STAT protein, protein interaction domain; STAT proteins (Signal Transducers and Activators of ...
2-119 3.37e-53

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


Pssm-ID: 460728  Cd Length: 119  Bit Score: 179.72  E-value: 3.37e-53
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338     2 AQWNQLQQLDTRYLEQLHQLYSDSFPMELRQFLAPWIESQDWAYAASKESHATLVFHNLLGEIDQQYSRFLQESNVLYQH 81
Cdd:pfam02865   1 SLWAQLQQLDGEALEQVQQLYGDHFPIEVRHYLAQWIESQDWEDAAQDESLATVLFHALLSELDSQASRFVQEDNFLLKH 80
                          90       100       110
                  ....*....|....*....|....*....|....*...
gi 21618338    82 NLRRIKQFLQSRYLEKPMEIARIVARCLWEESRLLQTA 119
Cdd:pfam02865  81 KLREIAKNLQSRYQENPLELARIIRNCLREERRILQEA 118
SH2_STAT4 cd10375
Src homology 2 (SH2) domain found in signal transducer and activator of transcription (STAT) ...
564-710 1.45e-52

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


Pssm-ID: 198238  Cd Length: 148  Bit Score: 179.31  E-value: 1.45e-52
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 564 WLDNIIDLVKKYILALWNEGYIMGFISKERERAILSTKPPGTFLLRFSESSKeGGVTFTWVEKDISGKTQIQSVEPYTKQ 643
Cdd:cd10375   1 WLEAILDLIKKHILPLWIDGYIMGFVSKEKERLLLKDKMPGTFLLRFSESHL-GGITFTWVDQSENGEVRFHSVEPYNKG 79
                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 21618338 644 QLNNMSFAEIIMGYKIMDATNILVSPLVYLYPDIPKEEAFGK-YCRPESQEHPEADPGAAPYLKTKFI 710
Cdd:cd10375  80 RLSALPFADILRDYKVIMAENIPENPLKYLYPDIPKDKAFGKhYSSQPCEVSRPTERGDKGYVPSVFI 147
STAT_bind pfam02864
STAT protein, DNA binding domain; STAT proteins (Signal Transducers and Activators of ...
325-464 5.45e-52

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


Pssm-ID: 460727  Cd Length: 132  Bit Score: 177.01  E-value: 5.45e-52
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338   325 RQPcmpmhpdrPLVIKTGVQFTTKVRLLVKFP---ELNYQLKIKVCIDKDSGDVAALRGSRKFNILG--TNTKVMNMEES 399
Cdd:pfam02864   1 KQP--------PQVLKTNTKFSVTVRLLVGLPlniELNPQVKVKIVSEKQARELQQIKGFRKFNISGeiLNNKALLEYES 72
                          90       100       110       120       130       140
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 21618338   400 NNGSLSAEFKHLTLREQRCGNGgrancDASLIVTEELHLITFETEVYHQGLKIDLETHSLPVVVI 464
Cdd:pfam02864  73 QNGGLSAEFRNLSLKEIKRGER-----KGSLSVTEEKFALLFETQFTLGGLVFDLWTLSLPVVVI 132
SH2_STAT_family cd09919
Src homology 2 (SH2) domain found in signal transducer and activator of transcription (STAT) ...
564-689 6.09e-51

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


Pssm-ID: 198175  Cd Length: 115  Bit Score: 173.54  E-value: 6.09e-51
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 564 WLDNIIDLVKKYILALWNEGYIMGFISKERERAILSTKPPGTFLLRFSESSkEGGVTFTWVEKDISGKTQIQSVEPYTKQ 643
Cdd:cd09919   1 WFFAIMLLTKRHLLKLWQDGLIMGFISKEEAEDLLKKKPPGTFLLRFSDSE-LGGITIAWVNEDPDGQSQVIHLQPYTKK 79
                        90       100       110       120
                ....*....|....*....|....*....|....*....|....*.
gi 21618338 644 QLNNMSFAEIIMGYKimdatnilvsPLVYLYPDIPKEEAFGKYCRP 689
Cdd:cd09919  80 DLDIRSLADRIRDLP----------QLVYLYPDIPKDEAFGKYYSP 115
STAT2_CCD cd16852
Coiled-coil domain of Signal Transducer and Activator of Transcription 2 (STAT2); This family ...
141-317 7.37e-42

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


Pssm-ID: 341077  Cd Length: 172  Bit Score: 150.24  E-value: 7.37e-42
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 141 QQMLEQHLQDVRKRVQDLEQKMKVVENLQDDFDFNYKTLKSQGdmqdlNGNNQSVTRQKMQQLEQMLTALDQMRRSIVSE 220
Cdd:cd16852   2 QHEIEKRINDLKTRIQCLEHSIRQLEDLQDTFDFKYKTHTMDK-----STSPDDKQTKQQQILQGMLNELDRFRKEVLSK 76
                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 221 LAGLLSAMEYVQKtLTDEELADWKRRQQIACIGGPPNICLDRLENWITSLAESQLQTRQQIKKLEELQQKVSYKGDPIVQ 300
Cdd:cd16852  77 MKVLLGRRDTLRE-LLLEELVEWKRRQQKACIGAPDDTSLEQLEKWFTKVAECLFQLRKFLKKLEELMGKVSYEHDPLKK 155
                       170
                ....*....|....*..
gi 21618338 301 HRPMLEERIVELFRNLM 317
Cdd:cd16852 156 QKPLLQQRVDELLTSLL 172
SH2_STAT2 cd10373
Src homology 2 (SH2) domain found in signal transducer and activator of transcription (STAT) 2 ...
564-713 1.44e-40

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


Pssm-ID: 198236  Cd Length: 151  Bit Score: 145.81  E-value: 1.44e-40
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 564 WLDNIIDLVKKYILALWNEGYIMGFISKERERAILSTKPPGTFLLRFSESSkEGGVTFTWVEKDISGKTQIQSVEPYTKQ 643
Cdd:cd10373   1 WLDKILELVHDHLKDLWKDGRIMGFVSRNQERRLLKKTISGTFLLRFSETS-EGGITCSWVEHQDDDKVLIYSVQPYTKE 79
                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 21618338 644 QLNNMSFAEIIMGYKIMDATNILVSPLVYLYPDIPKEEAFGKYC--RPESQEHPEadpgaapYLKTKFICVT 713
Cdd:cd10373  80 VLQSLPLTEIIRHYQLLTEENIPENPLRFLYPRIPRDEAFGCYYqeKVNLEEREK-------YLKHKLIVVS 144
STAT4_CCD cd16854
Coiled-coil domain of Signal Transducer and Activator of Transcription 4 (STAT4); This family ...
141-316 4.17e-40

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


Pssm-ID: 341079  Cd Length: 173  Bit Score: 145.39  E-value: 4.17e-40
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 141 QQMLEQHLQDVRKRVQDLEQKMKVVENLQDDFDFNYKTLKSqgdMQDLNGNNQSVtRQKMQQLEQMLTALDQMRRSIVSE 220
Cdd:cd16854   1 QRNVEHKVSAIKNSVQMTDQDTKYLEDLQDEFDFRYKTIQT---MDQGDKNSILM-KQEVTTLQEMLNSLDFKRKEALSK 76
                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 221 LAGLLSAMEYVQKTLTDEELADWKRRQQIACIGGPPNICLDRLENWITSLAESQLQTRQQIKKLEELQQKVSYKGDPIVQ 300
Cdd:cd16854  77 MTQIINEIDLLMSSMLTEELKDWKRRQQIACIGGPLHGGLDQLQNWFTLLAESLFQLRRQLEKLDELSTKVTYEGDPIPL 156
                       170
                ....*....|....*.
gi 21618338 301 HRPMLEERIVELFRNL 316
Cdd:cd16854 157 QRPQLLERVTFLIYNL 172
STAT_CCD cd14786
Coiled-coil domain of Signal Transducer and Activator of Transcription (STAT), also called ...
196-317 1.25e-34

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


Pssm-ID: 341075  Cd Length: 125  Bit Score: 128.18  E-value: 1.25e-34
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 196 TRQKMQQLEQMLTALDQMRRSIVSELAGLLSAMEYVQKTLTDEELADWKRRQQIACIGGPPNICLDRLENWITSLAESQL 275
Cdd:cd14786  10 LRNEFQILWEELKSLQQKRKEVLVKLLRRLLMAEEIQQELIIEELKNWKRRQQLAGNGAPREQSLDELQNWFESLAEFLW 89
                        90       100       110       120
                ....*....|....*....|....*....|....*....|..
gi 21618338 276 QTRQQIKKLEELQqkvsykGDPIVQHRPMLEERIVELFRNLM 317
Cdd:cd14786  90 QLRQQVKKLLELF------GDPIDPQLNDLLERVQELQKNLV 125
SH2_STAT6 cd10377
Src homology 2 (SH2) domain found in signal transducer and activator of transcription (STAT) 6 ...
564-695 3.10e-32

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


Pssm-ID: 198240  Cd Length: 129  Bit Score: 121.44  E-value: 3.10e-32
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 564 WLDNIIDLVKKYILALWNEGYIMGFISKERERAILSTKPPGTFLLRFSEsSKEGGVTFTWVEKDISGKTQIQSVEPYTKQ 643
Cdd:cd10377   1 WFDGVLDLTKRCLRSYWSDRLIIGFISKQYVTSLLLNEPDGTFLLRFSD-SEIGGITIAHVIRGQDGSPQIENIQPFSAK 79
                        90       100       110       120       130
                ....*....|....*....|....*....|....*....|....*....|..
gi 21618338 644 QLNNMSfaeiiMGYKIMDatnilVSPLVYLYPDIPKEEAFGKYCRPESQEHP 695
Cdd:cd10377  80 DLSIRS-----LGDRIRD-----LAQLKNLYPKKPKDEAFRSHYKPEQMKDG 121
STAT5_CCD cd16855
Coiled-coil domain of Signal Transducer and Activator of Transcription 5 (STAT5); This family ...
144-319 9.80e-26

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


Pssm-ID: 341080 [Multi-domain]  Cd Length: 194  Bit Score: 105.04  E-value: 9.80e-26
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 144 LEQHLQDVRKRVQDLEQKMKVVENLQDDFDFNY-KTLKSQGDMQDLNGNNQSVTRQKMQQLEQMLTALDQMRRSIVSELA 222
Cdd:cd16855   6 IRQQLEELRQRTQETENDLRNLQQKQESFVIQYqESQKIQAQLQQLQQQPQNERIELEQQLQQQKEQLEQLLNAKAQELL 85
                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 223 GL-LSAMEYVQKTLT----------DEELADWKRRQQIACIGGPPNICLDRLENWITSLAESQLQTRQQIKKLEELQQKV 291
Cdd:cd16855  86 QLrMELADKFKKTIQllsklqsrvlDEELIQWKRQQQLAGNGAPFESNLDTIQEWCESLAEIIWQNRQQIKRAERLKQKL 165
                       170       180
                ....*....|....*....|....*....
gi 21618338 292 SYKGDPIVQHR-PMLEERIVELFRNLMKS 319
Cdd:cd16855 166 PIPLPPEQKDMlPILNKQITDLLSSLVTS 194
SH2_STAT5b cd10420
Src homology 2 (SH2) domain found in signal transducer and activator of transcription (STAT) ...
564-722 2.08e-21

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


Pssm-ID: 198283  Cd Length: 145  Bit Score: 91.29  E-value: 2.08e-21
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 564 WLDNIIDLVKKYILALWNEGYIMGFISKERERAILSTKPPGTFLLRFSEsSKEGGVTFTWveKDISGKTQIQSVEPYTKQ 643
Cdd:cd10420   1 WFDGVMEVLKKHLKPHWNDGAILGFVNKQQAHDLLINKPDGTFLLRFSD-SEIGGITIAW--KFDSQERMFWNLMPFTTR 77
                        90       100       110       120       130       140       150
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....
gi 21618338 644 QLNNMSFAEiimgyKIMDatnilVSPLVYLYPDIPKEEAFGKYCRPESQEhPEADPGAAPYLKTKFICVTPTTCSNTID 722
Cdd:cd10420  78 DFSIRSLAD-----RLGD-----LNYLIYVFPDRPKDEVYSKYYTPVPCE-PATAKAVDGYVKPQIKQVVPEFVSASAD 145
SH2_STAT5 cd10376
Src homology 2 (SH2) domain found in signal transducer and activator of transcription (STAT) 5 ...
564-706 4.37e-21

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


Pssm-ID: 198239  Cd Length: 137  Bit Score: 90.03  E-value: 4.37e-21
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 564 WLDNIIDLVKKYILALWNEGYIMGFISKERERAILSTKPPGTFLLRFSEsSKEGGVTFTWveKDISGKTQIQSVEPYTKQ 643
Cdd:cd10376   1 WFDGVMEVLKKHLKPHWNDGAILGFVNKQQAHDLLINKPDGTFLLRFSD-SEIGGITIAW--KFDSPDRALWNLMPFTTR 77
                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|...
gi 21618338 644 QLNNMSFAEiimgyKIMDatnilVSPLVYLYPDIPKEEAFGKYCRPESQEHPEADPGAAPYLK 706
Cdd:cd10376  78 DFSIRSLAD-----RLGD-----LNYLIYVFPDRPKDEVFSKYYTPVLCNPSAVDGYVKPQIK 130
SH2_STAT5a cd10421
Src homology 2 (SH2) domain found in signal transducer and activator of transcription (STAT) ...
564-704 4.50e-20

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


Pssm-ID: 198284  Cd Length: 140  Bit Score: 87.02  E-value: 4.50e-20
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 564 WLDNIIDLVKKYILALWNEGYIMGFISKERERAILSTKPPGTFLLRFSEsSKEGGVTFTWveKDISGKTQIQSVEPYTKQ 643
Cdd:cd10421   1 WFDGVMEVLKKHHKPHWNDGAILGFVNKQQAHDLLINKPDGTFLLRFSD-SEIGGITIAW--KFDSPDRNLWNLKPFTTR 77
                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|....*..
gi 21618338 644 QLNNMSFAEiimgyKIMDatnilVSPLVYLYPDIPKEEAFGKYCRP------ESQEHPEADPGAAPY 704
Cdd:cd10421  78 DFSIRSLAD-----RLGD-----LNYLIYVFPDRPKDEVFSKYYTPvlakavDGYVKPQIKQVVPEF 134
STAT5_DBD cd16849
DNA-binding domain of Signal Transducer and Activator of Transcription 5 (STAT5); This family ...
321-481 3.15e-16

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


Pssm-ID: 341087  Cd Length: 159  Bit Score: 76.77  E-value: 3.15e-16
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 321 FVVERQPcmpmhpdrPLVIKTGVQFTTKVRLLVKfPELNYQL---KIKVCIDKDSGDVAALRGSRKF------NILgTNT 391
Cdd:cd16849   1 FIIEKQP--------PQVLKTQTRFAATVRLLVG-GKLNVHMnppQVKATIISEQQAKALLKNENITrnetsgEIL-NNC 70
                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 392 KVMNMEESNnGSLSAEFKHLTLREQRcgnggRANCDASLIVTEELHLITFETE--VYHQGLKIDLETHSLPVVVISNICQ 469
Cdd:cd16849  71 GVMEYHQAT-GQLSVSFRNMSLKRIK-----RADKRGAESVTEEKFTILFQSQfsVGGNELVFQVWTLSLPVVVIVHGNQ 144
                       170
                ....*....|..
gi 21618338 470 MPNAWASILWYN 481
Cdd:cd16849 145 ESNATATVLWDN 156
SH2 pfam00017
SH2 domain;
584-674 5.71e-13

SH2 domain;


Pssm-ID: 425423 [Multi-domain]  Cd Length: 77  Bit Score: 64.54  E-value: 5.71e-13
                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338   584 YIMGFISK-ERERAILSTKPPGTFLLRFSESSKeGGVTFTWVEKDisgktqiqSVEPYTKQQLNNmsfaeiiMGYKIMDA 662
Cdd:pfam00017   1 WYHGKISRqEAERLLLNGKPDGTFLVRESESTP-GGYTLSVRDDG--------KVKHYKIQSTDN-------GGYYISGG 64
                          90
                  ....*....|...
gi 21618338   663 -TNILVSPLVYLY 674
Cdd:pfam00017  65 vKFSSLAELVEHY 77
STAT6_CCD cd16856
Coiled-coil domain of Signal Transducer and Activator of Transcription 6 (STAT6); This family ...
147-324 2.35e-10

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


Pssm-ID: 341081  Cd Length: 167  Bit Score: 59.78  E-value: 2.35e-10
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 147 HLQDVRKRVQDLEQKMkvvENLQDDFDFNYKTLKSQGDMQDLNGNNQSVTRQKMQQLEQMLTALDQmrrSIVSELAGLLs 226
Cdd:cd16856   2 EKAAVLLRPQHLPLSI---HQLQEELKFDVENLELQHRVGQIHRLQLSLQQEKKSERIQQQEANGT---SPLQERAQLL- 74
                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 227 aMEYVQ-----KTLTDEELADWKRRQQIACIGGPPNICLDRLENWITSLAESQLQTRQQIkkleelqqkVSYKGDPIVQH 301
Cdd:cd16856  75 -QEAVGeleqaQSQVLKRIQIWKRQQQLAGNGAPFDENLSPLQTRCEQLVDVNFQLRQEV---------MLAGGELGSEL 144
                       170       180
                ....*....|....*....|...
gi 21618338 302 RPMLEERIVELFRNLMKSAFVVE 324
Cdd:cd16856 145 LSTLQERLNSLLQTLIQSSLVVE 167
STAT6_DBD cd16850
DNA-binding domain of Signal Transducer and Activator of Transcription 6 (STAT6); This family ...
321-481 1.38e-08

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


Pssm-ID: 341088  Cd Length: 160  Bit Score: 54.50  E-value: 1.38e-08
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 321 FVVERQPcmpmhpdrPLVIKTGVQFTTKVRLLVKFPELN-----YQLKIKVCIDKDSGDVAALRGSRKFN-----ILgtN 390
Cdd:cd16850   1 FLVEKQP--------PQVLKTQTKFQAGVRFLLGLRFLGapakpPLVRADMVTEKQARELSQPQGPGAGNentgeII--N 70
                        90       100       110       120       130       140       150       160
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 391 TKVMNMEESNNGSLSAEFKHLTLRE-QRCGNGGrancdaSLIVTEELHLITFETEVYHQG--LKIDLETHSLPVVVISNI 467
Cdd:cd16850  71 NTVPLENNITSKCCCATFKNLLLKKiKRCERKG------SESVTEEKCAVLFSADFTLGPgkLPIQLQALSLPVVVIVHG 144
                       170
                ....*....|....
gi 21618338 468 CQMPNAWASILWYN 481
Cdd:cd16850 145 NQDNNAKATILWDN 158
SH2 smart00252
Src homology 2 domains; Src homology 2 domains bind phosphotyrosine-containing polypeptides ...
586-639 1.94e-04

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


Pssm-ID: 214585 [Multi-domain]  Cd Length: 84  Bit Score: 40.68  E-value: 1.94e-04
                           10        20        30        40        50
                   ....*....|....*....|....*....|....*....|....*....|....
gi 21618338    586 MGFISKERERAILSTKPPGTFLLRFSESSKeGGVTFTWVEKDISGKTQIQSVEP 639
Cdd:smart00252   5 HGFISREEAEKLLKNEGDGDFLVRDSESSP-GDYVLSVRVKGKVKHYRIRRNED 57
SH2 cd00173
Src homology 2 (SH2) domain; In general, SH2 domains are involved in signal transduction; they ...
584-615 3.02e-04

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


Pssm-ID: 198173 [Multi-domain]  Cd Length: 79  Bit Score: 40.13  E-value: 3.02e-04
                        10        20        30
                ....*....|....*....|....*....|..
gi 21618338 584 YIMGFISKERERAILSTKPPGTFLLRFSESSK 615
Cdd:cd00173   2 WFHGSISREEAERLLRGKPDGTFLVRESSSEP 33
SPEC cd00176
Spectrin repeats, found in several proteins involved in cytoskeletal structure; family members ...
116-248 5.73e-03

Spectrin repeats, found in several proteins involved in cytoskeletal structure; family members include spectrin, alpha-actinin and dystrophin; the spectrin repeat forms a three helix bundle with the second helix interrupted by proline in some sequences; the repeats are independent folding units; tandem repeats are found in differing numbers and arrange in an antiparallel manner to form dimers; the repeats are defined by a characteristic tryptophan (W) residue in helix A and a leucine (L) at the carboxyl end of helix C and separated by a linker of 5 residues; two copies of the repeat are present here


Pssm-ID: 238103 [Multi-domain]  Cd Length: 213  Bit Score: 38.97  E-value: 5.73e-03
                        10        20        30        40        50        60        70        80
                ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 21618338 116 LQTAATAAQQGGQANHPTAAVVTEKQQMLEQHLQDVRKRVQD----LEQKMKVVENLQDDFDFNY--KTLKSQGDMQDLN 189
Cdd:cd00176  56 VEALNELGEQLIEEGHPDAEEIQERLEELNQRWEELRELAEErrqrLEEALDLQQFFRDADDLEQwlEEKEAALASEDLG 135
                        90       100       110       120       130       140
                ....*....|....*....|....*....|....*....|....*....|....*....|.
gi 21618338 190 GNNQSVTRQ--KMQQLEQMLTALDQMRRSIVSELAGLLSAMEYVQKTLTDEELADWKRRQQ 248
Cdd:cd00176 136 KDLESVEELlkKHKELEEELEAHEPRLKSLNELAEELLEEGHPDADEEIEEKLEELNERWE 196
 
Blast search parameters
Data Source: Precalculated data, version = cdd.v.3.21
Preset Options:Database: CDSEARCH/cdd   Low complexity filter: no  Composition Based Adjustment: yes   E-value threshold: 0.01

References:

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