SOCS3 Exerts Its Inhibitory Function on Interleukin-6 Signal Transduction through the SHP2 Recruitment Site of gp130

Interleukin-6 is involved in the regulation of many biological activities such as gene expression, cell proliferation, and differentiation. The control of the termination of cytokine signaling is as important as the regulation of initiation of signal transduction pathways. Three families of proteins involved in the down-regulation of cytokine signaling have been described recently: (i) SH2 domain-containing protein-tyrosine phosphatases (SHP), (ii) suppressors of cytokine signaling (SOCS), and (iii) protein inhibitors of activated STATs (PIAS). We have analyzed the interplay of two inhibitors in the signal transduction pathway of interleukin-6 and demonstrate that the tyrosine phosphatase SHP2 and SOCS3 do not act independently but are functionally linked. The activation of one inhibitor modulates the activity of the other; Inhibition of SHP2 activation leads to increased SOCS3-mRNA levels, whereas increased expression of SOCS3 results in a reduction of SHP2 phosphorylation after activation of the interleukin-6 signal transduction pathway. Furthermore, we show that tyrosine 759 in gp130 is essential for both SHP2 and SOCS3 but not for SOCS1 to exert their inhibitory activities on interleukin-6 signal transduction. Besides SHP2, SOCS3 also interacts with the Tyr(P)-759 peptide of gp130. Taken together, our results suggest differences in the function of SOCS1 and SOCS3 and a link between SHP2 and SOCS3. Interleukin-6 is involved in the regulation of many biological activities such as gene expression, cell proliferation, and differentiation. The control of the termination of cytokine signaling is as important as the regulation of initiation of signal transduction pathways. Three families of proteins involved in the down-regulation of cytokine signaling have been described recently: (i) SH2 domain-containing protein-tyrosine phosphatases (SHP), (ii) suppressors of cytokine signaling (SOCS), and (iii) protein inhibitors of activated STATs (PIAS). We have analyzed the interplay of two inhibitors in the signal transduction pathway of interleukin-6 and demonstrate that the tyrosine phosphatase SHP2 and SOCS3 do not act independently but are functionally linked. The activation of one inhibitor modulates the activity of the other; Inhibition of SHP2 activation leads to increased SOCS3-mRNA levels, whereas increased expression of SOCS3 results in a reduction of SHP2 phosphorylation after activation of the interleukin-6 signal transduction pathway. Furthermore, we show that tyrosine 759 in gp130 is essential for both SHP2 and SOCS3 but not for SOCS1 to exert their inhibitory activities on interleukin-6 signal transduction. Besides SHP2, SOCS3 also interacts with the Tyr(P)-759 peptide of gp130. Taken together, our results suggest differences in the function of SOCS1 and SOCS3 and a link between SHP2 and SOCS3. interleukin Janus kinase signal transducer and activator of transcription SH2-containing protein-tyrosine phosphatase 2 suppressor of cytokine signaling Src homology domain 2 glutathione S-transferase acute phase protein cytokine-inducible SH2 protein mitogen-activated protein kinase protein inhibitor of activated STATS Interleukin-6 exerts its biological activities through a receptor complex composed of the IL-61binding subunit gp80 and a dimer of the signal transducing receptor subunit gp130 (for review see Ref. 1.Heinrich P.C. Behrmann I. Müller-Newen G. Schaper F. Graeve L. Biochem. J. 1998; 334: 297-314Crossref PubMed Scopus (1757) Google Scholar). After ligand binding and gp130 dimer formation, constitutively associated kinases of the Janus family Jak1, Jak2, and tyrosine kinase 2 become activated by autophosphorylation. gp130, subsequently tyrosine phosphorylated on its cytoplasmic tail, recruits the transcription factors of the family of signal transducers and activators of transcription (STAT1 and STAT3) (2.Lütticken 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 (713) Google Scholar, 3.Stahl 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 (849) Google Scholar) and the protein-tyrosine phosphatase SHP2 (4.Stahl N. Farruggella T.J. Boulton T.G. Zhong Z. Darnell Jr., J.E. Yancopoulos G.D. Science. 1995; 267: 1349-1353Crossref PubMed Scopus (869) Google Scholar) via specific phosphotyrosine-SH2 domain interactions (5.Heim M.H. Kerr I.M. Stark G.R. Darnell Jr., J.E. Science. 1995; 267: 1347-1349Crossref PubMed Scopus (352) Google Scholar, 6.Hemmann U. Gerhartz C. Heesel B. Sasse J. Kurapkat G. Grötzinger J. Wollmer A. Zhong Z. Darnell Jr., J.E. Graeve L. Heinrich P.C. Horn F. J. Biol. Chem. 1996; 271: 12999-13007Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar). In turn, these signaling components become tyrosine-phosphorylated also. Jak1 has been described to be crucial for the activation of gp130, the STAT factors (7.Guschin D. Rogers N. Briscoe J. Witthuhn B. Watling D. Horn F. Pellegrini S. Yasukawa K. Heinrich P. Stark G.R. Ihle J.N. Kerr I.M. EMBO J. 1995; 14: 1421-1429Crossref PubMed Scopus (365) Google Scholar), and SHP2 (8.Schaper F. Gendo C. Eck M. Schmitz J. Grimm C. Anhuf D. Kerr I.M. Heinrich P.C. Biochem. J. 1998; 335: 557-565Crossref PubMed Scopus (143) Google Scholar). The tyrosine-phosphorylated STATs form homo- and/or heterodimers (9.Zhong Z. Wen Z. Darnell Jr., J.E. Science. 1994; 264: 95-98Crossref PubMed Scopus (1735) Google Scholar) and translocate to the nucleus where they bind to enhancer elements of interleukin-6 inducible genes (10.Wegenka U.M. Buschmann J. Lütticken C. Heinrich P.C. Horn F. Mol. Cell. Biol. 1993; 13: 276-288Crossref PubMed Scopus (490) Google Scholar). The Jak/STAT signal transduction pathway is under negative control by several different mechanisms. The presence of a nuclear phosphatase leading to dephosphorylation of activated STAT1 has been proposed by Haspel et al. (11.Haspel R.L. Salditt-Georgieff M. Darnell Jr., J.E. EMBO J. 1996; 15: 6262-6268Crossref PubMed Scopus (272) Google Scholar). These authors observed a quantitative recycling of dephosphorylated STAT1 from the nucleus to the cytoplasm implicating a circulation of STAT factors between the cytoplasm and the nucleus. These data contradict those of Kim and Maniatis (12.Kim T.K. Maniatis T. Science. 1996; 273: 1717-1719Crossref PubMed Scopus (361) Google Scholar) who demonstrated a proteasome-dependent loss of activated STAT1 in the nucleus. Recently, another group of IL-6 signaling inhibitors has been described, STAT-binding proteins, known as protein inhibitors of activated STATs (PIAS) (13.Chung C.D. Liao J.Y. Liu B. Rao X.P. Jay P. Berta P. Shuai K. Science. 1997; 278: 1803-1805Crossref PubMed Scopus (809) Google Scholar, 14.Liu B. Liao J.Y. Rao X.P. Kushner S.A. Chung C.D. Chang D.D. Shuai K. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 10626-10631Crossref PubMed Scopus (636) Google Scholar). Although the PIAS do not contain phosphotyrosine binding domains such as SH2 or PTB domains, they associate with activated, tyrosine-phosphorylated STATs, leading to a loss of STAT-DNA binding activity. The mechanism of this highly specific interaction of protein inhibitor of activated STATs with activated STAT factors remains to be elucidated. Another new family of inhibitors of cytokine signaling has been discovered in three different laboratories, recently. These proteins are referred to as suppressors of cytokine signaling (SOCS) (15.Starr R. Willson T.A. Viney E.M. Murray L.J. Rayner J.R. Jenkins B.J. Gonda T.J. Alexander W.S. D. 1997; PubMed Scopus Google Scholar), proteins T.A. M. M. R. K. A. S. M. T. N. T. T. S. A. 1997; PubMed Scopus Google Scholar), or STAT inhibitors T. M. M. T. S. A. N. T. Taga T. K. S. Kishimoto T. 1997; PubMed Scopus Google Scholar). The of this family contain a SH2 domain as as a domain the on the cell and SOCS3 expression to be by the proteins the phosphorylation of Janus gp130 and STAT they are as inhibitors of IL-6 SOCS1 the kinase activity of the three Janus kinases Jak1, Jak2, and tyrosine kinase 2 involved in IL-6 signaling (15.Starr R. Willson T.A. Viney E.M. Murray L.J. Rayner J.R. Jenkins B.J. Gonda T.J. Alexander W.S. D. 1997; PubMed Scopus Google Scholar, T.A. M. M. R. K. A. S. M. T. N. T. T. S. A. 1997; PubMed Scopus Google Scholar, T. M. M. T. S. A. N. T. Taga T. K. S. Kishimoto T. 1997; PubMed Scopus Google Scholar). Recently, has been described that SOCS1 to phosphotyrosine the kinase domain of activated M. A. T. S. T. T. Ihle J.N. A. EMBO J. PubMed Scopus Google Scholar). the protein-tyrosine phosphatase SHP2 to IL-6 signal transduction. of the IL-6 receptor complex leads to a of SHP2 to tyrosine 759 in gp130 and to its tyrosine phosphorylation (4.Stahl N. Farruggella T.J. Boulton T.G. Zhong Z. Darnell Jr., J.E. Yancopoulos G.D. Science. 1995; 267: 1349-1353Crossref PubMed Scopus (869) Google Scholar). SHP2 activation is a crucial for the of the mitogen-activated protein kinase pathway IL-6 T. M. M. T. K. T. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). of in gp130 results in and STAT1 and activation and in increased gene (8.Schaper F. Gendo C. Eck M. Schmitz J. Grimm C. Anhuf D. Kerr I.M. Heinrich P.C. Biochem. J. 1998; 335: 557-565Crossref PubMed Scopus (143) Google Scholar, A. N. S.A. Farruggella T. T. T. Yancopoulos G. Biol. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, Mol. Cell. Biol. 1998; PubMed Scopus Google Scholar). SOCS3 is by IL-6 (15.Starr R. Willson T.A. Viney E.M. Murray L.J. Rayner J.R. Jenkins B.J. Gonda T.J. Alexander W.S. D. 1997; PubMed Scopus Google Scholar, T.A. M. M. R. K. A. S. M. T. N. T. T. S. A. 1997; PubMed Scopus Google Scholar, T. M. M. T. S. A. N. T. Taga T. K. S. Kishimoto T. 1997; PubMed Scopus Google Scholar) and SHP2 is activated (4.Stahl N. Farruggella T.J. Boulton T.G. Zhong Z. Darnell Jr., J.E. Yancopoulos G.D. Science. 1995; 267: 1349-1353Crossref PubMed Scopus (869) Google Scholar), we these proteins in to expression or tyrosine phosphorylation We observed that of SHP2 activation to of SOCS3 the the expression of the SOCS3 protein the of tyrosine-phosphorylated SHP2 after IL-6 Furthermore, we that but not the SHP2 in gp130 to exert its negative function on the IL-6 signal transduction pathway. is demonstrated in the that both SHP2 and SOCS3 with a phosphotyrosine peptide the of gp130. Although we demonstrate we also to show that binding of SOCS3 to of gp130 not on the presence of from and and by from a of J. and K. of by J. The the and to gp130 from J. to the and STAT1 from and to SHP2 and from from and from IL-6 and as described O. U. A. Müller-Newen G. J. S. P. S. Heinrich P.C. J. Biochem. 1995; PubMed Scopus Google Scholar, R. P. F. 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Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar). with to a of the gene in the the receptor in the of of SOCS1 or SOCS3 to a reduction in gene the of gene expression that SOCS1 and SOCS3 also transcription in In and SOCS1 and SOCS3 but are inhibitors for acute phase protein gene by SHP2 the acute phase protein gene (8.Schaper F. Gendo C. Eck M. Schmitz J. Grimm C. Anhuf D. Kerr I.M. Heinrich P.C. Biochem. J. 1998; 335: 557-565Crossref PubMed Scopus (143) Google Scholar, A. N. S.A. Farruggella T. T. T. Yancopoulos G. Biol. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, C. Heesel B. Sasse J. U. C. J. Horn F. Heinrich P.C. Graeve L. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar). the interplay of the IL-6 signal transduction inhibitors and SHP2, we SHP2 also the expression of SOCS1 and SOCS3 do not gp130 M. M. M. Yasukawa K. M. Taga T. Kishimoto T. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar), with gp130 receptor expression of the by cell with the domain of gp130 and to be for 2 of the receptor to a of SOCS3 as in 2 The data to 2 of SOCS1 in not of a of the SHP2 in gp130 by a of to in increased SOCS3 with the The tyrosine 759 in the cytoplasmic of gp130 not to of the SOCS3 These that SHP2 activation SOCS3 gene SOCS3 SHP2 with SOCS3 expression SHP2 phosphorylation after with analyzed by of SOCS3 to a SHP2 phosphorylation with not with We from these data that SOCS3 also signaling are negative of the IL-6 signal transduction pathway. SOCS1 interacts with the kinase domain of activated T.A. M. M. R. K. A. S. M. T. N. T. T. S. A. 1997; PubMed Scopus Google Scholar, M. A. T. S. T. T. Ihle J.N. A. EMBO J. PubMed Scopus Google Scholar, Willson T.A. A. R. M. Alexander W.S. D. EMBO J. PubMed Scopus Google Scholar). the a of with SOCS3 has been described by et al. R. Yasukawa M. T. A. K. S. A. A. 1998; PubMed Scopus Google Scholar). SOCS3 not kinase activity in Willson T.A. A. R. M. Alexander W.S. D. EMBO J. PubMed Scopus Google Scholar). the mechanism of of we SOCS3 activity on the activation of SHP2 and the of SOCS1 and SOCS3 to acute phase protein gene in the presence or of tyrosine 759 in gp130. or in with or gene to those described of in gp130 to to gene as from described (8.Schaper F. Gendo C. Eck M. Schmitz J. Grimm C. Anhuf D. Kerr I.M. Heinrich P.C. Biochem. J. 1998; 335: 557-565Crossref PubMed Scopus (143) Google Scholar) with the expression of SOCS1 or SOCS3 to of the activity of the receptor SOCS3 to gene in the of a activity after expression of SOCS3. SOCS3 but not SOCS1 the SHP2 in gp130 to exert its inhibitory on acute phase protein gene the of in gp130 for SOCS3 we the reduction of activation (15.Starr R. Willson T.A. Viney E.M. Murray L.J. Rayner J.R. Jenkins B.J. Gonda T.J. Alexander W.S. D. 1997; PubMed Scopus Google Scholar, T.A. M. M. R. K. A. S. M. T. N. T. T. S. 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PubMed Scopus Google Scholar) on in gp130. with or with of STAT tyrosine phosphorylation in and and binding in analyzed after receptor In these SOCS3 to be in and STAT1 phosphorylation in the presence of in the of in the cytoplasmic of gp130. results with STAT activation of the cytoplasmic of gp130 is to SOCS3 In STAT activation through the receptor to SOCS3 of of also to a STAT activation in the receptor by a in the presence of of to a reduction of and STAT1 tyrosine phosphorylation and and binding activity after The of SOCS1 to STAT activation not by a of tyrosine 759 in gp130. these we that the of STAT1 and activation by but not by in gp130. the inhibitory activities of both SHP2 and SOCS3 on in gp130, to SOCS3 interacts with this SHP2 from of with of SOCS3 the interaction of SHP2 with SOCS3 the with to the of SOCS3 a of SHP2 observed after not is that the for the of SOCS3 with the complex SOCS3 SH2 domain we this protein is to with phosphotyrosine 759 in gp130. cell of or with to the of gp130 in its phosphorylated or form and of the with The analyzed for SOCS3 and SHP2 by SOCS3 SHP2 with the peptide SOCS3 with the phosphotyrosine peptide from of with SHP2 with the Tyr(P)-759 from both cell SOCS3 is to form a complex with the peptide the phosphorylated of gp130. In to SOCS1 not with In a as the one for we SHP2 binding to the SOCS1 in the of the as demonstrated by of SOCS1 with the phosphotyrosine to the cytoplasmic tyrosine of gp130, demonstrate that the Tyr(P)-759 peptide is to bind SOCS3 and SHP2 binding of SOCS1 to of the phosphotyrosine observed data suggest that SOCS3 is with the peptide Tyr(P)-759 by binding to the peptide or by binding through we the interaction on the presence of SHP2 of SOCS3 or from and with the Tyr(P)-759 and as with or peptide to binding to the The analyzed by peptide Tyr(P)-759 to bind SHP2 and SOCS3 the for the phosphorylated tyrosine of gp130. In a we SHP2 with the Tyr(P)-759 peptide and this subsequently with of or control interaction of SOCS3 with the peptide Tyr(P)-759 be SHP2 binding to the peptide not by the with SOCS3. the of SHP2 for the SHP2 from of SOCS3 by with SHP2 a control the SHP2 The SOCS3 is in the The of the is in The of SHP2 and SOCS3 in the by a with SHP2 and the of SOCS3 the of SHP2 and the presence of SOCS3 in the this for the with the phosphotyrosine peptide 759 of gp130 is from this that SHP2 is not for SOCS3 binding to the Tyr(P)-759 The specific binding of SOCS3 to the phosphotyrosine peptide Tyr(P)-759 that this interaction is of the this interaction in we a protein the of SOCS3 in this of SOCS3 has been to contain the SH2 domain (15.Starr R. Willson T.A. Viney E.M. Murray L.J. Rayner J.R. Jenkins B.J. Gonda T.J. Alexander W.S. D. 1997; PubMed Scopus Google Scholar, T.A. M. M. R. K. A. S. M. T. N. T. T. S. A. 1997; PubMed Scopus Google Scholar, T. M. M. T. S. A. N. T. Taga T. K. S. Kishimoto T. 1997; PubMed Scopus Google Scholar, M. A. T. S. T. T. Ihle J.N. A. EMBO J. PubMed Scopus Google Scholar). The protein with to the of gp130 in phosphorylated or The peptide analyzed for by a binding of the protein observed with the tyrosine-phosphorylated peptide SHP2, and SOCS3 are of cytokine signaling (8.Schaper F. Gendo C. Eck M. Schmitz J. Grimm C. Anhuf D. Kerr I.M. Heinrich P.C. Biochem. J. 1998; 335: 557-565Crossref PubMed Scopus (143) Google R. Willson T.A. Viney E.M. Murray L.J. Rayner J.R. Jenkins B.J. Gonda T.J. Alexander W.S. D. 1997; PubMed Scopus Google Scholar, T.A. M. M. R. K. A. S. M. T. N. T. T. S. A. 1997; PubMed Scopus Google Scholar, T. M. M. T. S. A. N. T. Taga T. K. S. Kishimoto T. 1997; PubMed Scopus Google Scholar, A. N. S.A. Farruggella T. T. T. Yancopoulos G. Biol. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, Mol. Cell. Biol. 1998; PubMed Scopus Google Scholar). In the we have on the interplay of these proteins in IL-6 signal transduction. We for the a and link between SHP2 and SOCS3 and differences in the of of SOCS1 and SOCS3. The inhibitory of SHP2 on the IL-6 signal transduction pathway on in gp130 (8.Schaper F. Gendo C. Eck M. Schmitz J. Grimm C. Anhuf D. Kerr I.M. Heinrich P.C. Biochem. J. 1998; 335: 557-565Crossref PubMed Scopus (143) Google Scholar, A. N. S.A. Farruggella T. T. T. Yancopoulos G. Biol. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, Mol. Cell. Biol. 1998; PubMed Scopus Google Scholar). we that the presence of in gp130 is also crucial for the inhibitory function of SOCS3 and of by the inhibitory activity of SOCS3 on both STAT1 and activation as as on acute phase protein gene The function of is not by this in gp130, the specific of for SOCS3 activity. The for this is that the inhibitory activity of SOCS3 on the interaction of its SH2 domain with Tyr(P)-759 in the receptor we to demonstrate that but not with the Tyr(P)-759 of gp130. SHP2 also to this peptide The interaction of SOCS3 with the cytoplasmic of gp130 be or via We have for the of function of SHP2 for SOCS3. we SOCS3 or through SHP2 to the Tyr(P)-759 The of SHP2 not SOCS3 binding to the Tyr(P)-759 receptor peptide Furthermore, we to demonstrate that the protein the domain to phosphotyrosine Tyr(P)-759 of gp130 These results show that SHP2 is not for binding of SOCS3 to the gp130 receptor In has been described that SHP2 acute phase protein gene activation by down-regulation of STAT phosphorylation (8.Schaper F. Gendo C. Eck M. Schmitz J. Grimm C. Anhuf D. Kerr I.M. Heinrich P.C. Biochem. J. 1998; 335: 557-565Crossref PubMed Scopus (143) Google Scholar, A. N. S.A. Farruggella T. T. T. Yancopoulos G. Biol. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, Mol. Cell. 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PubMed Scopus Google Scholar). SOCS1 and SOCS3 to exert their inhibitory on the Jak/STAT pathway by different as by our results and the that but not in in kinase M. A. T. S. T. T. Ihle J.N. A. EMBO J. PubMed Scopus Google Scholar, Willson T.A. A. R. M. Alexander W.S. D. EMBO J. PubMed Scopus Google Scholar). In et al. S. Yasukawa A. A. S. T. I. M. A. PubMed Scopus Google Scholar) not these differences but a of SOCS1 SOCS3 to bind Furthermore, the kinase inhibitory of SOCS3 in of the kinase inhibitory of SOCS1 S. Yasukawa A. A. S. T. I. M. A. PubMed Scopus Google Scholar). The of the data in this is the that in to has to be to the receptor complex to IL-6 signal transduction. the of IL-6 signaling by SOCS3 be of different mechanisms. SOCS3 activity via binding of the domain to the activation of the SOCS3 be to gp130, to Tyr(P)-759 or by binding to the SHP2, leading to the of through the kinase inhibitory of is in with the of et al. S. Yasukawa A. A. S. T. I. M. A. PubMed Scopus Google Scholar). SOCS3 gene expression is by IL-6 and SOCS3 SOCS3 as a inhibitor (15.Starr R. Willson T.A. Viney E.M. Murray L.J. Rayner J.R. Jenkins B.J. Gonda T.J. Alexander W.S. D. 1997; PubMed Scopus Google Scholar, T.A. M. M. R. K. A. S. M. T. N. T. T. S. A. 1997; PubMed Scopus Google Scholar, T. M. M. T. S. A. N. T. Taga T. K. S. Kishimoto T. 1997; PubMed Scopus Google Scholar). We not a after with this not that SOCS1 also IL-6 signaling via another pathway. has been proposed that SHP2 phosphorylation results in in activity R. J. A. Science. 1993; PubMed Scopus Google Scholar), in also signal transduction by signaling SHP2 activation by the of in the gp130 receptor with SOCS3 gene Furthermore, SOCS3 not act on this receptor as inhibitor of its a reduction in SHP2 activation be by in SOCS3 the SOCS3 expression leads to a of SHP2 phosphorylation be of the of by SOCS3 or by of SHP2 and SOCS3 for Tyr(P)-759 of gp130. expression of SOCS3 be by a of phosphorylated are to show tyrosine phosphorylation of SHP2 modulates SOCS3 activity. is not tyrosine in SHP2 are phosphorylated after of the IL-6 signal transduction pathway. The activator has been to the Jak/STAT pathway N. T. 1998; PubMed Scopus Google Scholar, T.K. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: PubMed Scopus Google Scholar). from our L. P. Schaper F. Heinrich P.C. Graeve L. J. Biol. Chem. Full Text Full Text PDF Scopus Google Scholar) that the inhibitory function of on IL-6 signal transduction also on the presence of in gp130. of in gp130 to the of to STAT also SOCS3 gene is that exerts its via SOCS3 activity also on Tyr(P)-759 in gp130 as described in the is to that SHP2 exerts of its negative function on the Jak/STAT pathway through the of SOCS3 to the activated receptor this are in We and for the and and for the phosphotyrosine We also for and and Graeve for the