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• W1989792012 abstract "Activation of Stat proteins by cytokines is initiated by their Src homology 2 (SH2) domain-mediated association with the cytokine receptors. Previously, we identified an essential role of the coiled-coil domain of Stat3 in binding of the receptor peptides derived from the interleukin-6 receptor subunit, gp130. In this study, we further investigated the molecular basis of this regulation. We found that the C-terminal domain of Stat3 negatively regulates its receptor binding activity only in the absence of the first α-helix of the coiled-coil domain, which leads to a hypothesis of intramolecular interaction. Physical interactions between the coiled-coil domain and the C-terminal domain, as well as the SH2 domain, were indeed detected. Furthermore, a sub-region of the C-terminal domain (amino acids 720–740), which is also involved in the interaction with the coiled-coil domain, was demonstrated to be critical for the regulation of the receptor binding. Correspondingly, phosphorylation on Ser-727 within this region inhibits this interaction. In agreement with the peptide binding results, both the coiled-coil domain and the C-terminal sub-region are necessary for the functional recruitment of Stat3 to the cellular gp130 in response to interleukin-6, suggesting that the interdomain interaction is a prerequisite for the SH2-mediated receptor binding in interleukin-6 signaling. Activation of Stat proteins by cytokines is initiated by their Src homology 2 (SH2) domain-mediated association with the cytokine receptors. Previously, we identified an essential role of the coiled-coil domain of Stat3 in binding of the receptor peptides derived from the interleukin-6 receptor subunit, gp130. In this study, we further investigated the molecular basis of this regulation. We found that the C-terminal domain of Stat3 negatively regulates its receptor binding activity only in the absence of the first α-helix of the coiled-coil domain, which leads to a hypothesis of intramolecular interaction. Physical interactions between the coiled-coil domain and the C-terminal domain, as well as the SH2 domain, were indeed detected. Furthermore, a sub-region of the C-terminal domain (amino acids 720–740), which is also involved in the interaction with the coiled-coil domain, was demonstrated to be critical for the regulation of the receptor binding. Correspondingly, phosphorylation on Ser-727 within this region inhibits this interaction. In agreement with the peptide binding results, both the coiled-coil domain and the C-terminal sub-region are necessary for the functional recruitment of Stat3 to the cellular gp130 in response to interleukin-6, suggesting that the interdomain interaction is a prerequisite for the SH2-mediated receptor binding in interleukin-6 signaling. STAT 1The abbreviations used are: STATsignal transducers and activators of transcriptionaaamino acid(s)JAKJanus kinaseSH2Src homology 2N-domainN-terminal domainIFNinterferonILinterleukinPBSphosphate-buffered salineERKextracellular signal-regulated kinaseGSTglutathione S-transferase 1The abbreviations used are: STATsignal transducers and activators of transcriptionaaamino acid(s)JAKJanus kinaseSH2Src homology 2N-domainN-terminal domainIFNinterferonILinterleukinPBSphosphate-buffered salineERKextracellular signal-regulated kinaseGSTglutathione S-transferase (forsignal transducer and activator oftranscription) represents a family of latent cytoplasmic transcription factors. Seven mammalian STAT genes have been identified so far, and over 40 different polypeptides, including most cytokines and certain growth factors, are known to activate one or more STATs (reviewed in Refs. 1Darnell J.E., Jr. Science. 1997; 277: 1630-1635Crossref PubMed Scopus (3345) Google Scholar, 2Ihle J.N. Cell. 1996; 84: 331-334Abstract Full Text Full Text PDF PubMed Scopus (1262) Google Scholar, 3Schindler C. Darnell J.E., Jr. Annu. Rev. Biochem. 1995; 64: 621-651Crossref PubMed Scopus (1640) Google Scholar). Stat3 was originally identified as an acute-phase response factor activated by IL-6 in mouse liver, and also by homology to Stat1 (4Akira S. Nishio Y. Inoue M. Wang X.J. Wei S. Matsusaka T. Yoshida K. Sudo T. Naruto M. Kishimoto T. Cell. 1994; 77: 63-71Abstract Full Text PDF PubMed Scopus (864) Google Scholar, 5Zhong Z. Wen Z. Darnell J.E., Jr. Science. 1994; 264: 95-98Crossref PubMed Scopus (1691) Google Scholar). IL-6-type cytokines play pleiotropic roles in immune response, hematopoiesis, and neuronal differentiation (6Van Snick J. Annu. Rev. Immunol. 1990; 8: 253-278Crossref PubMed Google Scholar). This family comprises IL-6, IL-11, leukemia inhibitory factor, oncostatin M, ciliary neurotrophic factor, and cardiotrophin, which share receptor gp130 as a common subunit and are able to stimulate Stat3 (7Lütticken C. Wegenka U.M. Yuan J. Buschmann J. Schindler C. Ziemiecki A. Harpur A.G. Wilks A.F. Yasukawa K. Taga T. Kishimoto T. Barbieri G. Pellegrini S. Sendtner M. Heinrich P.C. Horn F. Science. 1994; 263: 89-92Crossref PubMed Scopus (704) Google Scholar, 8Stahl N. Boulton T.G. Farruggella T. Ip N.Y. Davis S. Witthuhn B.A. Quelle F.W. Silvennoinen O. Barbieri G. Pellegrini S. Ihle J.N. Yancopoulos G.D. Science. 1994; 263: 92-95Crossref PubMed Scopus (840) Google Scholar). Binding of IL-6 to its receptor gp80 (subunit α) induces the homodimerization of gp130 (subunit β) and trans-phosphorylation of the gp130-associated JAKs (7Lütticken C. Wegenka U.M. Yuan J. Buschmann J. Schindler C. Ziemiecki A. Harpur A.G. Wilks A.F. Yasukawa K. Taga T. Kishimoto T. Barbieri G. Pellegrini S. Sendtner M. Heinrich P.C. Horn F. Science. 1994; 263: 89-92Crossref PubMed Scopus (704) Google Scholar, 8Stahl N. Boulton T.G. Farruggella T. Ip N.Y. Davis S. Witthuhn B.A. Quelle F.W. Silvennoinen O. Barbieri G. Pellegrini S. Ihle J.N. Yancopoulos G.D. Science. 1994; 263: 92-95Crossref PubMed Scopus (840) Google Scholar, 9Murakami M. Hibi M. Nakagawa N. Nakagawa T. Yasukawa K. Yamanishi K. Taga T. Kishimoto T. Science. 1993; 260: 1808-1810Crossref PubMed Scopus (638) Google Scholar). Activated Jak1 phosphorylates six tyrosine residues on the cytoplasmic domain of gp130. Whereas the second membrane-proximal tyrosine residue (Y2) is required for recruitment of the SH2-containing phosphatase-2, any one of the four tyrosine residues (Y3–Y6) containing the consensus Y XXQ motif serves as a docking site for Stat3 binding upon IL-6 stimulation (10Stahl N. Farruggella T.J. Boulton T.G. Zhong Z. Darnell J.E., Jr. Yancopoulos G.D. Science. 1995; 267: 1349-1353Crossref PubMed Scopus (864) Google Scholar, 11Hemmann U. Gerhartz C. Heesel B. Sasse J. Kurapkat G. Grötzinger J. Wollmer A. Zhong Z. Darnell J.E., Jr. Graeve L. Heinrich P.C. Horn F. J. Biol. Chem. 1996; 271: 12999-13007Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar, 12Fukada T. Hibi M. Yamanaka Y. Takahashi-Tezuka M. Fujitani Y. Yamaguchi T. Nakajima K. Hirano T. Immunity. 1996; 5: 449-460Abstract Full Text Full Text PDF PubMed Scopus (583) Google Scholar). The receptor bound Stat3 is subsequently phosphorylated by Jak1 on a single tyrosine residue 705 at the C terminus. Stat3 forms dimers via the reciprocal interactions between its SH2 domain and the phosphorylated tyrosine 705, translocates into the nucleus, binds to DNA, and regulates the expression of their target genes leading to various cellular responses (3Schindler C. Darnell J.E., Jr. Annu. Rev. Biochem. 1995; 64: 621-651Crossref PubMed Scopus (1640) Google Scholar, 13Heim M.H. Kerr I.M. Stark G.R. Darnell J.E., Jr. Science. 1995; 267: 1347-1349Crossref PubMed Scopus (347) Google Scholar, 14Shuai K. Horvath C.M. Huang L.H. Qureshi S.A. Cowburn D. Darnell J.E., Jr. Cell. 1994; 76: 821-828Abstract Full Text PDF PubMed Scopus (677) Google Scholar, 15Silvennoinen O. Schindler C. Schlessinger J. Levy D.E. Science. 1993; 261: 1736-1739Crossref PubMed Scopus (296) Google Scholar). Although the recruitment of Stat3 to gp130 is the first and critical step for its subsequent activation, the regulation of Stat3 receptor binding has been remained largely unknown.STAT proteins share a highly conserved structure with a number of functional domains. The three-dimensional structure of the N-terminal domain (N-domain) of Stat4 contains 130 amino acids was first resolved (16Vinkemeier U. Moarefi I. Darnell J.E., Jr. Kuriyan J. Science. 1998; 279: 1048-1052Crossref PubMed Scopus (212) Google Scholar). This domain was originally identified to be involved in tetramer formation, but recently also reported to affect the induction of Stat4 tyrosine phosphorylation stimulated by IFN-α (17Xu X. Sun Y.L. Hoey T. Science. 1996; 273: 794-797Crossref PubMed Scopus (405) Google Scholar, 18Murphy T.L. Geissal E.D. Farrar J.D. Murphy K.M. Mol. Cell. Biol. 2000; 20: 7121-7131Crossref PubMed Scopus (43) Google Scholar). Subsequently, the crystal structures of the DNA bound homodimers of truncated Stat1 and Stat3β, lacking the N-domain and the most of the C-terminal domain, have been reported and exhibit highly similar structures and conserved domains (19Chen X. Vinkemeier U. Zhao Y. Jeruzalmi D. Darnell J.E., Jr. Kuriyan J. Cell. 1998; 93: 827-839Abstract Full Text Full Text PDF PubMed Scopus (542) Google Scholar, 20Becker S. Groner B. Müller C.M. Nature. 1998; 394: 145-151Crossref PubMed Scopus (655) Google Scholar). Two new domains have been revealed: an N-terminal coiled-coil domain containing four antiparallel α-helices, and a linker domain located between the DNA binding domain and the SH2 domain. The C-terminal domain comprises the transcriptional activation domain (21Bhattacharya S. Eckner R. Grossman S. Oldread E. Arany Z. D'Andrea A. Livingston D.M. Nature. 1996; 383: 344-347Crossref PubMed Scopus (419) Google Scholar) and is also involved in the proteasome-dependent turnover in Stat5 (22Wang D.M. Moriggl R. Stravopodis D. Carpino N. Marine J.-C. Teglund S. Feng J. Ihle J.N. EMBO J. 2000; 19: 392-399Crossref PubMed Google Scholar). However, the very C-terminal region, including 40–50 amino acids, is absent in both crystal structures (19Chen X. Vinkemeier U. Zhao Y. Jeruzalmi D. Darnell J.E., Jr. Kuriyan J. Cell. 1998; 93: 827-839Abstract Full Text Full Text PDF PubMed Scopus (542) Google Scholar, 20Becker S. Groner B. Müller C.M. Nature. 1998; 394: 145-151Crossref PubMed Scopus (655) Google Scholar). The linker domain is reported to be important in the transcriptional activity in Stat1 (23Yang E. Wen Z. Haspel R.L. Zhang J.J. Darnell J.E., Jr. Mol. Cell. Biol. 1999; 19: 5106-5112Crossref PubMed Scopus (46) Google Scholar), whereas the coiled-coil structure has often been inferred to be involved in protein-protein interaction (24Kammerer R.A. Matrix Biol. 1997; 15: 555-565Crossref PubMed Scopus (66) Google Scholar). Indeed, Lys-161 in the helix α1 of Stat1 interacts with p48, a protein from an IFN response factor family, to form interferon-stimulated gene factor 3 complex that regulates IFN-α-responsive genes (25Horvath C.M. Stark G.R. Kerr I.M. Darnell J.E., Jr. Mol. Cell. Biol. 1996; 16: 6957-6964Crossref PubMed Scopus (160) Google Scholar). A short region in the first α-helix of Stat3 has been demonstrated to associate with another transcription factor, c-Jun, which cooperatively activates transcription of IL-6 inducible α2-macroglobulin gene (26Zhang X. Wrzeszczynska M.H. Horvath C.M. Darnell J.E., Jr. Mol. Cell. Biol. 1999; 19: 7138-7146Crossref PubMed Scopus (184) Google Scholar). In addition, the coiled-coil domain of Stat5 associates with Nmi, an N-Myc interactor, which augments Stat5-mediated transcription (27Zhu M. John S. Berg M. Leonard W. Cell. 1999; 96: 121-130Abstract Full Text Full Text PDF PubMed Scopus (253) Google Scholar). However, the possible effect of the coiled-coil domain on the activation of Stat protein itself has not been studied. Recently, we have reported that removal of the first α-helix, or mutation of the highly conserved Asp-170 or Lys-177 residue, in the first α-helix of the coiled-coil domain of Stat3 results in a loss of the SH2 domain-mediated binding of gp130 (28Zhang T. Kee W.H. Seow K.T. Fung W. Cao X. Mol. Cell. Biol. 2000; 20: 7132-7139Crossref PubMed Scopus (97) Google Scholar). The data demonstrated a novel role of the coiled-coil domain of Stat3 in the regulation of its receptor binding and the subsequent activation in response to IL-6 and epidermal growth factor. Based on the crystal structure of the Stat3 dimer, the coiled-coil and SH2 domains are separated by the DNA binding and linker domains (19Chen X. Vinkemeier U. Zhao Y. Jeruzalmi D. Darnell J.E., Jr. Kuriyan J. Cell. 1998; 93: 827-839Abstract Full Text Full Text PDF PubMed Scopus (542) Google Scholar, 20Becker S. Groner B. Müller C.M. Nature. 1998; 394: 145-151Crossref PubMed Scopus (655) Google Scholar). These results suggest that the coiled-coil domain is able to remotely influence the SH2 function through an undetermined mechanism.In the present study, experiments were performed to investigate the molecular basis of this novel regulation. We have identified that deletion of the first α-helix in the coiled-coil domain abrogates its binding activity. However, further removal of 70 amino acids (700–770) at the C terminus of this mutant restores the impaired binding activity, suggesting a possible interaction of the coiled-coil domain and the C-terminal domain. Such interaction is indeed observed. Furthermore, a sub-region of C-terminal domain was demonstrated to be critical for regulation of the receptor binding and is also essential for the interaction with the coiled-coil domain. Experimental results support the proposed model of the domain-domain interaction and indicate its physiological relevance in the functional recruitment of Stat3 to the gp130 receptor subunit in IL-6 signaling. STAT 1The abbreviations used are: STATsignal transducers and activators of transcriptionaaamino acid(s)JAKJanus kinaseSH2Src homology 2N-domainN-terminal domainIFNinterferonILinterleukinPBSphosphate-buffered salineERKextracellular signal-regulated kinaseGSTglutathione S-transferase 1The abbreviations used are: STATsignal transducers and activators of transcriptionaaamino acid(s)JAKJanus kinaseSH2Src homology 2N-domainN-terminal domainIFNinterferonILinterleukinPBSphosphate-buffered salineERKextracellular signal-regulated kinaseGSTglutathione S-transferase (forsignal transducer and activator oftranscription) represents a family of latent cytoplasmic transcription factors. Seven mammalian STAT genes have been identified so far, and over 40 different polypeptides, including most cytokines and certain growth factors, are known to activate one or more STATs (reviewed in Refs. 1Darnell J.E., Jr. Science. 1997; 277: 1630-1635Crossref PubMed Scopus (3345) Google Scholar, 2Ihle J.N. Cell. 1996; 84: 331-334Abstract Full Text Full Text PDF PubMed Scopus (1262) Google Scholar, 3Schindler C. Darnell J.E., Jr. Annu. Rev. Biochem. 1995; 64: 621-651Crossref PubMed Scopus (1640) Google Scholar). Stat3 was originally identified as an acute-phase response factor activated by IL-6 in mouse liver, and also by homology to Stat1 (4Akira S. Nishio Y. Inoue M. Wang X.J. Wei S. Matsusaka T. Yoshida K. Sudo T. Naruto M. Kishimoto T. Cell. 1994; 77: 63-71Abstract Full Text PDF PubMed Scopus (864) Google Scholar, 5Zhong Z. Wen Z. Darnell J.E., Jr. Science. 1994; 264: 95-98Crossref PubMed Scopus (1691) Google Scholar). IL-6-type cytokines play pleiotropic roles in immune response, hematopoiesis, and neuronal differentiation (6Van Snick J. Annu. Rev. Immunol. 1990; 8: 253-278Crossref PubMed Google Scholar). This family comprises IL-6, IL-11, leukemia inhibitory factor, oncostatin M, ciliary neurotrophic factor, and cardiotrophin, which share receptor gp130 as a common subunit and are able to stimulate Stat3 (7Lütticken C. Wegenka U.M. Yuan J. Buschmann J. Schindler C. Ziemiecki A. Harpur A.G. Wilks A.F. Yasukawa K. Taga T. Kishimoto T. Barbieri G. Pellegrini S. Sendtner M. Heinrich P.C. Horn F. Science. 1994; 263: 89-92Crossref PubMed Scopus (704) Google Scholar, 8Stahl N. Boulton T.G. Farruggella T. Ip N.Y. Davis S. Witthuhn B.A. Quelle F.W. Silvennoinen O. Barbieri G. Pellegrini S. Ihle J.N. Yancopoulos G.D. Science. 1994; 263: 92-95Crossref PubMed Scopus (840) Google Scholar). Binding of IL-6 to its receptor gp80 (subunit α) induces the homodimerization of gp130 (subunit β) and trans-phosphorylation of the gp130-associated JAKs (7Lütticken C. Wegenka U.M. Yuan J. Buschmann J. Schindler C. Ziemiecki A. Harpur A.G. Wilks A.F. Yasukawa K. Taga T. Kishimoto T. Barbieri G. Pellegrini S. Sendtner M. Heinrich P.C. Horn F. Science. 1994; 263: 89-92Crossref PubMed Scopus (704) Google Scholar, 8Stahl N. Boulton T.G. Farruggella T. Ip N.Y. Davis S. Witthuhn B.A. Quelle F.W. Silvennoinen O. Barbieri G. Pellegrini S. Ihle J.N. Yancopoulos G.D. Science. 1994; 263: 92-95Crossref PubMed Scopus (840) Google Scholar, 9Murakami M. Hibi M. Nakagawa N. Nakagawa T. Yasukawa K. Yamanishi K. Taga T. Kishimoto T. Science. 1993; 260: 1808-1810Crossref PubMed Scopus (638) Google Scholar). Activated Jak1 phosphorylates six tyrosine residues on the cytoplasmic domain of gp130. Whereas the second membrane-proximal tyrosine residue (Y2) is required for recruitment of the SH2-containing phosphatase-2, any one of the four tyrosine residues (Y3–Y6) containing the consensus Y XXQ motif serves as a docking site for Stat3 binding upon IL-6 stimulation (10Stahl N. Farruggella T.J. Boulton T.G. Zhong Z. Darnell J.E., Jr. Yancopoulos G.D. Science. 1995; 267: 1349-1353Crossref PubMed Scopus (864) Google Scholar, 11Hemmann U. Gerhartz C. Heesel B. Sasse J. Kurapkat G. Grötzinger J. Wollmer A. Zhong Z. Darnell J.E., Jr. Graeve L. Heinrich P.C. Horn F. J. Biol. Chem. 1996; 271: 12999-13007Abstract Full Text Full Text PDF PubMed Scopus (147) Google Scholar, 12Fukada T. Hibi M. Yamanaka Y. Takahashi-Tezuka M. Fujitani Y. Yamaguchi T. Nakajima K. Hirano T. Immunity. 1996; 5: 449-460Abstract Full Text Full Text PDF PubMed Scopus (583) Google Scholar). The receptor bound Stat3 is subsequently phosphorylated by Jak1 on a single tyrosine residue 705 at the C terminus. Stat3 forms dimers via the reciprocal interactions between its SH2 domain and the phosphorylated tyrosine 705, translocates into the nucleus, binds to DNA, and regulates the expression of their target genes leading to various cellular responses (3Schindler C. Darnell J.E., Jr. Annu. Rev. Biochem. 1995; 64: 621-651Crossref PubMed Scopus (1640) Google Scholar, 13Heim M.H. Kerr I.M. Stark G.R. Darnell J.E., Jr. Science. 1995; 267: 1347-1349Crossref PubMed Scopus (347) Google Scholar, 14Shuai K. Horvath C.M. Huang L.H. Qureshi S.A. Cowburn D. Darnell J.E., Jr. Cell. 1994; 76: 821-828Abstract Full Text PDF PubMed Scopus (677) Google Scholar, 15Silvennoinen O. Schindler C. Schlessinger J. Levy D.E. Science. 1993; 261: 1736-1739Crossref PubMed Scopus (296) Google Scholar). Although the recruitment of Stat3 to gp130 is the first and critical step for its subsequent activation, the regulation of Stat3 receptor binding has been remained largely unknown. signal transducers and activators of transcription amino acid(s) Janus kinase Src homology 2 N-terminal domain interferon interleukin phosphate-buffered saline extracellular signal-regulated kinase glutathione S-transferase signal transducers and activators of transcription amino acid(s) Janus kinase Src homology 2 N-terminal domain interferon interleukin phosphate-buffered saline extracellular signal-regulated kinase glutathione S-transferase STAT proteins share a highly conserved structure with a number of functional domains. The three-dimensional structure of the N-terminal domain (N-domain) of Stat4 contains 130 amino acids was first resolved (16Vinkemeier U. Moarefi I. Darnell J.E., Jr. Kuriyan J. Science. 1998; 279: 1048-1052Crossref PubMed Scopus (212) Google Scholar). This domain was originally identified to be involved in tetramer formation, but recently also reported to affect the induction of Stat4 tyrosine phosphorylation stimulated by IFN-α (17Xu X. Sun Y.L. Hoey T. Science. 1996; 273: 794-797Crossref PubMed Scopus (405) Google Scholar, 18Murphy T.L. Geissal E.D. Farrar J.D. Murphy K.M. Mol. Cell. Biol. 2000; 20: 7121-7131Crossref PubMed Scopus (43) Google Scholar). Subsequently, the crystal structures of the DNA bound homodimers of truncated Stat1 and Stat3β, lacking the N-domain and the most of the C-terminal domain, have been reported and exhibit highly similar structures and conserved domains (19Chen X. Vinkemeier U. Zhao Y. Jeruzalmi D. Darnell J.E., Jr. Kuriyan J. Cell. 1998; 93: 827-839Abstract Full Text Full Text PDF PubMed Scopus (542) Google Scholar, 20Becker S. Groner B. Müller C.M. Nature. 1998; 394: 145-151Crossref PubMed Scopus (655) Google Scholar). Two new domains have been revealed: an N-terminal coiled-coil domain containing four antiparallel α-helices, and a linker domain located between the DNA binding domain and the SH2 domain. The C-terminal domain comprises the transcriptional activation domain (21Bhattacharya S. Eckner R. Grossman S. Oldread E. Arany Z. D'Andrea A. Livingston D.M. Nature. 1996; 383: 344-347Crossref PubMed Scopus (419) Google Scholar) and is also involved in the proteasome-dependent turnover in Stat5 (22Wang D.M. Moriggl R. Stravopodis D. Carpino N. Marine J.-C. Teglund S. Feng J. Ihle J.N. EMBO J. 2000; 19: 392-399Crossref PubMed Google Scholar). However, the very C-terminal region, including 40–50 amino acids, is absent in both crystal structures (19Chen X. Vinkemeier U. Zhao Y. Jeruzalmi D. Darnell J.E., Jr. Kuriyan J. Cell. 1998; 93: 827-839Abstract Full Text Full Text PDF PubMed Scopus (542) Google Scholar, 20Becker S. Groner B. Müller C.M. Nature. 1998; 394: 145-151Crossref PubMed Scopus (655) Google Scholar). The linker domain is reported to be important in the transcriptional activity in Stat1 (23Yang E. Wen Z. Haspel R.L. Zhang J.J. Darnell J.E., Jr. Mol. Cell. Biol. 1999; 19: 5106-5112Crossref PubMed Scopus (46) Google Scholar), whereas the coiled-coil structure has often been inferred to be involved in protein-protein interaction (24Kammerer R.A. Matrix Biol. 1997; 15: 555-565Crossref PubMed Scopus (66) Google Scholar). Indeed, Lys-161 in the helix α1 of Stat1 interacts with p48, a protein from an IFN response factor family, to form interferon-stimulated gene factor 3 complex that regulates IFN-α-responsive genes (25Horvath C.M. Stark G.R. Kerr I.M. Darnell J.E., Jr. Mol. Cell. Biol. 1996; 16: 6957-6964Crossref PubMed Scopus (160) Google Scholar). A short region in the first α-helix of Stat3 has been demonstrated to associate with another transcription factor, c-Jun, which cooperatively activates transcription of IL-6 inducible α2-macroglobulin gene (26Zhang X. Wrzeszczynska M.H. Horvath C.M. Darnell J.E., Jr. Mol. Cell. Biol. 1999; 19: 7138-7146Crossref PubMed Scopus (184) Google Scholar). In addition, the coiled-coil domain of Stat5 associates with Nmi, an N-Myc interactor, which augments Stat5-mediated transcription (27Zhu M. John S. Berg M. Leonard W. Cell. 1999; 96: 121-130Abstract Full Text Full Text PDF PubMed Scopus (253) Google Scholar). However, the possible effect of the coiled-coil domain on the activation of Stat protein itself has not been studied. Recently, we have reported that removal of the first α-helix, or mutation of the highly conserved Asp-170 or Lys-177 residue, in the first α-helix of the coiled-coil domain of Stat3 results in a loss of the SH2 domain-mediated binding of gp130 (28Zhang T. Kee W.H. Seow K.T. Fung W. Cao X. Mol. Cell. Biol. 2000; 20: 7132-7139Crossref PubMed Scopus (97) Google Scholar). The data demonstrated a novel role of the coiled-coil domain of Stat3 in the regulation of its receptor binding and the subsequent activation in response to IL-6 and epidermal growth factor. Based on the crystal structure of the Stat3 dimer, the coiled-coil and SH2 domains are separated by the DNA binding and linker domains (19Chen X. Vinkemeier U. Zhao Y. Jeruzalmi D. Darnell J.E., Jr. Kuriyan J. Cell. 1998; 93: 827-839Abstract Full Text Full Text PDF PubMed Scopus (542) Google Scholar, 20Becker S. Groner B. Müller C.M. Nature. 1998; 394: 145-151Crossref PubMed Scopus (655) Google Scholar). These results suggest that the coiled-coil domain is able to remotely influence the SH2 function through an undetermined mechanism. In the present study, experiments were performed to investigate the molecular basis of this novel regulation. We have identified that deletion of the first α-helix in the coiled-coil domain abrogates its binding activity. However, further removal of 70 amino acids (700–770) at the C terminus of this mutant restores the impaired binding activity, suggesting a possible interaction of the coiled-coil domain and the C-terminal domain. Such interaction is indeed observed. Furthermore, a sub-region of C-terminal domain was demonstrated to be critical for regulation of the receptor binding and is also essential for the interaction with the coiled-coil domain. Experimental results support the proposed model of the domain-domain interaction and indicate its physiological relevance in the functional recruitment of Stat3 to the gp130 receptor subunit in IL-6 signaling. We thank Drs. J. E. Darnell for pRC/CMV-Stat3, R. Jove for Stat3β, Z. Zhao, E. Manser, and L. Lim for the pXJ40-FLAG and pXJ40-GST vectors. We are grateful to C. P. Lim and V. Novotny for reading the manuscript and helpful discussions." @default.
• W1989792012 created "2016-06-24" @default.
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• W1989792012 date "2002-05-01" @default.
• W1989792012 modified "2023-10-16" @default.
• W1989792012 title "Interdomain Interaction of Stat3 Regulates Its Src Homology 2 Domain-mediated Receptor Binding Activity" @default.
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