This family represents the C terminus of mammalian STAT6 (signal transducer and activator of transcription 6). It contains an LXXLL motif which binds to NCOA1 (Nuclear receptor coactivator 1) [].
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 upon IL-4-induced activation []. There is speculation that the inappropriate activation of STAT6 is involved in uncontrolled cell growth in an oncogenic state []. 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. It was shown that large scale chromatin remodeling of the IL-4 gene occurs as cells differentiate into Th2 effectors is STAT6 dependent []. This entry represents the SH2 domain of STAT6.STAT proteins have a dual function: signal transduction and activation of transcription. When cytokines are bound to cell surface receptors, the associated Janus kinases (JAKs) are activated, leading to tyrosine phosphorylation of the given STAT proteins []. Phosphorylated STATs form dimers, translocate to the nucleus, and bind specific response elements to activate transcription of target genes []. STAT proteins contain an N-terminal domain (NTD), a coiled-coil domain (CCD), a DNA-binding domain (DBD), an α-helical linker domain (LD), an SH2 domain, and a transactivation domain (TAD). The SH2 domain is necessary for receptor association and tyrosine phosphodimer formation. There are seven mammalian STAT family members which have been identified: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6 [].
TRAF3-interacting protein 1 (TRAF3IP1) recruits TRAF3 (tumour necrosis factor receptor-associated factor 3) and DISC1 (Disrupted-In-Schizophrenia 1) to the microtubules and is conserved from worms to humans []. The N-terminal region is the microtubule binding domain and is well-conserved; the C-terminal 100 residues, also well-conserved, constitute the coiled-coil region which binds to TRAF3. The central region of the protein is rich in lysine and glutamic acid and carries KKE motifs which may also be necessary for tubulin-binding, but this region is the least well-conserved []. In humans, it plays an inhibitory role on IL13 signaling by binding to IL13RA1. It is involved in suppression of IL13-induced STAT6 phosphorylation, transcriptional activity and DNA-binding [, ].
Nuclear receptor coactivator 1 (NCOA1, also known as SRC-1) belongs to the SRC/p160 nuclear receptor coactivator family, which contains proteins that are ligand-dependent transcription factors []. These receptors can function as molecular switches [].NCOA1 directly binds nuclear receptors and stimulates the transcriptional activities in a hormone-dependent fashion []. It is involved in the coactivation of different nuclear receptors, such as for steroids (PGR, GR and ER), retinoids (RXRs), thyroid hormone (TRs) and prostanoids (PPARs) []. It is also involved in coactivation mediated by STAT3, STAT5A, STAT5B and STAT6 transcription factors [, , ]. It plays a central role in creating multisubunit coactivator complexes that act via remodeling of chromatin, and possibly acts by participating in both chromatin remodeling and recruitment of general transcription factors []. It can be regulated by sumoylation and ubiquitination [].
TRAF3-interacting protein 1 (TRAF3IP1) recruits TRAF3 (tumour necrosis factor receptor-associated factor 3) and DISC1 (Disrupted-In-Schizophrenia 1) to the microtubules and is conserved from worms to humans []. The N-terminal region is the microtubule binding domain and is well-conserved; the C-terminal 100 residues, also well-conserved, constitute the coiled-coil region which binds to TRAF3. The central region of the protein is rich in lysine and glutamic acid and carries KKE motifs which may also be necessary for tubulin-binding, but this region is the least well-conserved []. In humans, it plays an inhibitory role on IL13 signaling by binding to IL13RA1. It is involved in suppression of IL13-induced STAT6 phosphorylation, transcriptional activity and DNA-binding [, ].This superfamily represents the N-terminal domain of TRAF3-interacting protein 1.
TRAF3-interacting protein 1 (TRAF3IP1) recruits TRAF3 (tumour necrosis factor receptor-associated factor 3) and DISC1 (Disrupted-In-Schizophrenia 1) to the microtubules and is conserved from worms to humans []. The N-terminal region is the microtubule binding domain and is well-conserved; the C-terminal 100 residues, also well-conserved, constitute the coiled-coil region which binds to TRAF3. The central region of the protein is rich in lysine and glutamic acid and carries KKE motifs which may also be necessary for tubulin-binding, but this region is the least well-conserved []. In humans, it plays an inhibitory role on IL13 signaling by binding to IL13RA1. It is involved in suppression of IL13-induced STAT6 phosphorylation, transcriptional activity and DNA-binding [, ].This entry represents the N-terminal domain of TRAF3-interacting protein 1.
This group represents the nuclear receptor coactivator family, also known as the SRC/p160 nuclear receptor coactivator family, which contains proteins that are ligand-dependent transcription factors []. These receptors can function as molecular switches [].NCOA1 directly binds nuclear receptors and stimulates the transcriptional activities in a hormone-dependent fashion []. It is involved in the coactivation of different nuclear receptors, such as for steroids (PGR, GR and ER), retinoids (RXRs), thyroid hormone (TRs) and prostanoids (PPARs) []. It is also involved in coactivation mediated by STAT3, STAT5A, STAT5B and STAT6 transcription factors [, , ]. It plays a central role in creating multisubunit coactivator complexes that act via remodeling of chromatin, and possibly acts by participating in both chromatin remodeling and recruitment of general transcription factors []. It can be regulated by sumoylation and ubiquitination []. NCOA2 is a transcriptional coactivator for steroid receptors and nuclear receptors. It functions as a coactivator of the steroid binding domain (AF-2) but not of the modulating N-terminal domain (AF-1) []. Together with NCOA1, it is required to control energy balance between white and brown adipose tissues []. NCOA3 is overexpressed in a fraction of breast cancers and has been linked to prognosis and tamoxifen resistance [, ].
This conserved domain of unknown function is usually found tandemly repeated in the nuclear receptor coactivator family (NCOA1/2/3), also known as the SRC/p160 nuclear receptor coactivator family, which are ligand-dependent transcription factors [, ].NCOA1 directly binds nuclear receptors and stimulates the transcriptional activities in a hormone-dependent fashion []. It is involved in the coactivation of different nuclear receptors, such as for steroids (PGR, GR and ER), retinoids (RXRs), thyroid hormone (TRs) and prostanoids (PPARs) []. It is also involved in coactivation mediated by STAT3, STAT5A, STAT5B and STAT6 transcription factors [, , ]. It plays a central role in creating multisubunit coactivator complexes that act via remodeling of chromatin, and possibly acts by participating in both chromatin remodeling and recruitment of general transcription factors []. It can be regulated by sumoylation and ubiquitination []. NCOA2 is a transcriptional coactivator for steroid receptors and nuclear receptors. It functions as a coactivator of the steroid binding domain (AF-2) but not of the modulating N-terminal domain (AF-1) []. Together with NCOA1, it is required to control energy balance between white and brown adipose tissues []. NCOA3 is overexpressed in a fraction of breast cancers and has been linked to prognosis and tamoxifen resistance [, ].
This entry represents the SH2 domain of STAT5b.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. They regulate B and T cell development [, ].STAT proteins have a dual function: signal transduction and activation of transcription. When cytokines are bound to cell surface receptors, the associated Janus kinases (JAKs) are activated, leading to tyrosine phosphorylation of the given STAT proteins []. Phosphorylated STATs form dimers, translocate to the nucleus, and bind specific response elements to activate transcription of target genes []. STAT proteins contain an N-terminal domain (NTD), a coiled-coil domain (CCD), a DNA-binding domain (DBD), an α-helical linker domain (LD), an SH2 domain, and a transactivation domain (TAD). The SH2 domain is necessary for receptor association and tyrosine phosphodimer formation. There are seven mammalian STAT family members which have been identified: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6 [].
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 []. This entry represents the SH2 domain of STAT2.STAT proteins have a dual function: signal transduction and activation of transcription. When cytokines are bound to cell surface receptors, the associated Janus kinases (JAKs) are activated, leading to tyrosine phosphorylation of the given STAT proteins []. Phosphorylated STATs form dimers, translocate to the nucleus, and bind specific response elements to activate transcription of target genes []. STAT proteins contain an N-terminal domain (NTD), a coiled-coil domain (CCD), a DNA-binding domain (DBD), an α-helical linker domain (LD), an SH2 domain, and a transactivation domain (TAD). The SH2 domain is necessary for receptor association and tyrosine phosphodimer formation. There are seven mammalian STAT family members which have been identified: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6 [].
STAT3 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. STAT3 has been shown to interact with Rho GTPases []Three alternatively spliced transcript variants encoding distinct isoforms have been described. STAT3 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 []. This entry represents the SH2 domain of STAT3.STAT proteins have a dual function: signal transduction and activation of transcription. When cytokines are bound to cell surface receptors, the associated Janus kinases (JAKs) are activated, leading to tyrosine phosphorylation of the given STAT proteins []. Phosphorylated STATs form dimers, translocate to the nucleus, and bind specific response elements to activate transcription of target genes []. STAT proteins contain an N-terminal domain (NTD), a coiled-coil domain (CCD), a DNA-binding domain (DBD), an α-helical linker domain (LD), an SH2 domain, and a transactivation domain (TAD). The SH2 domain is necessary for receptor association and tyrosine phosphodimer formation. There are seven mammalian STAT family members which have been identified: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6 [].
Signal transducer and activator of transcription 4 (STAT4) transduces interleukin-12, interleukin-23, and type I interferon cytokine signals in T cells and monocytes [, ]. It plays an important role in CD4+ Th1 lineage differentiation and IFN-gamma protein expression by CD4+ T cells []. It is crucial for both innate and adaptive immune responses to viral infection []. Variations of the STAT4 gene affect the susceptibility to autoimmune diseases [], such as systemic lupus erythematosus 11 (SLEB11) []and rheumatoid arthritis (RA) []. STAT proteins have a dual function: signal transduction and activation of transcription. When cytokines are boundto cell surface receptors, the associated Janus kinases (JAKs) are activated, leading to tyrosine phosphorylation of the given STAT proteins []. Phosphorylated STATs form dimers, translocate to the nucleus, and bind specific response elements to activate transcription of target genes []. STAT proteins contain an N-terminal domain (NTD), a coiled-coil domain (CCD), a DNA-binding domain (DBD), an α-helical linker domain (LD), an SH2 domain, and a transactivation domain (TAD). The SH2 domain is necessary for receptor association and tyrosine phosphodimer formation. There are seven mammalian STAT family members which have been identified: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6 []. This entry represents the SH2 domain of STAT4.
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 a heterodimer with STAT2 that can bind Interferon Stimulated Response Element (ISRE) promoter element in response to either IFN-alpha or IFN-beta stimulation [].STAT proteins have a dual function: signal transduction and activation of transcription. When cytokines are bound to cell surface receptors, the associated Janus kinases (JAKs) are activated, leading to tyrosine phosphorylation of the given STAT proteins []. Phosphorylated STATs form dimers, translocate to the nucleus, and bind specific response elements to activate transcription of target genes []. STAT proteins contain an N-terminal domain (NTD), a coiled-coil domain (CCD), a DNA-binding domain (DBD), an α-helical linker domain (LD), an SH2 domain, and a transactivation domain (TAD). The SH2 domain is necessary for receptor association and tyrosine phosphodimer formation. There are seven mammalian STAT family members which have been identified: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6 [].
This entry represents the RNA recognition motif 2 (RRM2) of poly [ADP-ribose]polymerase 14 (PARP-14), also termed aggressive lymphoma protein 2, a member of the B aggressive lymphoma (BAL) family of macrodomain-containing PARPs []. It is expressed in B lymphocytes and interacts with the IL-4-induced transcription factor Stat6. It plays a fundamental role in the regulation of IL-4-induced B-cell protection against apoptosis after irradiation or growth factor withdrawal. It mediates IL-4 effects on the levels of gene products that regulate cell survival, proliferation, and lymphomagenesis. PARP-14 acts as a transcriptional switch for Stat6-dependent gene activation. In the presence of IL-4, PARP-14 activates transcription by facilitating the binding of Stat6 to the promoter and release of HDACs from the promoter with an IL-4 signal. In contrast, in the absence of a signal, PARP-14 acts as a transcriptional repressor by recruiting HDACs []. Absence of PARP-14 protects against Myc-induced developmental block and lymphoma. Thus, PARP-14 may play an important role in Myc-induced oncogenesis []. Additional research indicates that PARP-14 is also a binding partner with phosphoglucose isomerase (PGI)/autocrine motility factor (AMF). It can inhibit PGI/AMF ubiquitination, thus contributing to its stabilization and secretion [].PARP-14 contains two N-terminal RNA recognition motifs (RRMs), three tandem macro domains, and C-terminal region with sequence homology to PARP catalytic domain.
Signal transducer and activator of transcription 4 (STAT4) transduces interleukin-12, interleukin-23, and type I interferon cytokine signals in T cells and monocytes [, ]. It plays an important role in CD4+ Th1 lineage differentiation and IFN-gamma protein expression by CD4+ T cells []. It is crucial for both innate and adaptive immune responses to viral infection []. Variations of the STAT4 gene affect the susceptibility to autoimmune diseases [], such as systemic lupus erythematosus 11 (SLEB11) []and rheumatoid arthritis (RA) []. STAT proteins have a dual function: signal transduction and activation of transcription. When cytokines are bound to cell surface receptors, the associated Janus kinases (JAKs) are activated, leading to tyrosine phosphorylation of the given STAT proteins []. Phosphorylated STATs form dimers, translocate to the nucleus, and bind specific response elements to activate transcription of target genes []. STAT proteins contain an N-terminal domain (NTD), a coiled-coil domain (CCD), a DNA-binding domain (DBD), an α-helical linker domain (LD), an SH2 domain, and a transactivation domain (TAD). The SH2 domain is necessary for receptor association and tyrosine phosphodimer formation. There are seven mammalian STAT family members which have been identified: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6 [].
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. They regulate B and T cell development [, ].STAT proteins have a dual function: signal transduction and activation of transcription. When cytokines are bound to cell surface receptors, the associated Janus kinases (JAKs) are activated, leading to tyrosine phosphorylation of the given STAT proteins []. Phosphorylated STATs form dimers, translocate to the nucleus, and bind specific response elements to activate transcription of target genes []. STAT proteins contain an N-terminal domain (NTD), a coiled-coil domain (CCD), a DNA-binding domain (DBD), an α-helical linker domain (LD), an SH2 domain, and a transactivation domain (TAD). The SH2 domain is necessary for receptor association and tyrosine phosphodimer formation. There are seven mammalian STAT family members which have been identified: STAT1, STAT2, STAT3, STAT4, STAT5 (STAT5A and STAT5B), and STAT6 [].
