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• W2065522904 abstract "gp130 is a signal-transducing subunit of receptors for the interleukin-6 (IL-6)-related cytokine subfamily including IL-6, leukemia inhibitory factor, oncostatin M, IL-11, and ciliary neurotrophic factor, indicating that gp130-mediated signals are involved in the immune response, hematopoiesis, inflammation, and endocrine and nervous system activity. We previously showed that gp130 stimulation rapidly activates Jak, Btk, and Tec tyrosine kinases, all of which constitutively associate with gp130. To further elucidate intracellular signal transduction through gp130, we examined the possible involvement of another nonreceptor tyrosine kinase, p92c-fes (Fes). We showed that gp130 stimulation rapidly induced tyrosine phosphorylation of Fes and actually activated its kinase activity in hematopoietic lineage cells. Furthermore, Fes associated with gp130 independently of ligand stimulation like Jak, Btk, and Tec tyrosine kinases. These results indicate that multiple nonreceptor tyrosine kinases are involved in the gp130-mediated signal transduction pathway. Because both gp130 and Fes are expressed not only in hematopoietic lineage cells but also in heart and nerve cells, Fes may play a role in signal transduction through gp130 in these tissues. gp130 is a signal-transducing subunit of receptors for the interleukin-6 (IL-6)-related cytokine subfamily including IL-6, leukemia inhibitory factor, oncostatin M, IL-11, and ciliary neurotrophic factor, indicating that gp130-mediated signals are involved in the immune response, hematopoiesis, inflammation, and endocrine and nervous system activity. We previously showed that gp130 stimulation rapidly activates Jak, Btk, and Tec tyrosine kinases, all of which constitutively associate with gp130. To further elucidate intracellular signal transduction through gp130, we examined the possible involvement of another nonreceptor tyrosine kinase, p92c-fes (Fes). We showed that gp130 stimulation rapidly induced tyrosine phosphorylation of Fes and actually activated its kinase activity in hematopoietic lineage cells. Furthermore, Fes associated with gp130 independently of ligand stimulation like Jak, Btk, and Tec tyrosine kinases. These results indicate that multiple nonreceptor tyrosine kinases are involved in the gp130-mediated signal transduction pathway. Because both gp130 and Fes are expressed not only in hematopoietic lineage cells but also in heart and nerve cells, Fes may play a role in signal transduction through gp130 in these tissues. gp130 was originally identified as a signal-transducing subunit of the IL-6 1The abbreviations used are: ILinterleukinIL-6RIL-6 receptorsIL-6Rαsoluble human IL-6 receptor αGM-CSFgranulocyte macrophage colony-stimulating factorPAGEPolyacrylamide gel electrophoresis. receptor (IL-6R) (1Taga T. Hibi M. Hirata Y. Yamasaki K. Yasukawa K. Matsuda T. Hirano T. Kishimoto T. Cell. 1989; 58: 573-581Abstract Full Text PDF PubMed Scopus (1194) Google Scholar, 2Hibi M. Murakami M. Saito M. Hirano T. Taga T. Kishimoto T. Cell. 1990; 63: 1149-1157Abstract Full Text PDF PubMed Scopus (1097) Google Scholar). Recent evidence has shown that gp130 functions as a subunit not only for IL-6R but also for receptors of the IL-6-related cytokine subfamily such as leukemia inhibitory factor, oncostatin M, IL-11, and ciliary neurotrophic factor (3Gearing D.P. Thut C.J. VanderBos T. Gimpel S.D. Delaney P.B. King J.A. Price V. Cosman D. Beckmann M.P. EMBO J. 1991; 10: 2839-2848Crossref PubMed Scopus (518) Google Scholar, 4Gearing D.P. Comeau M.R. Friend D.J. Gimpel S.D. Thut C.J. Mcgourty J. Brasher K.K. King J.A. Gills S. Mosley B. Ziagler S.F. Cosman D. Science. 1992; 255: 1434-1437Crossref PubMed Scopus (795) Google Scholar, 5Ip N.Y. Nye S.H. Boulton T.G. Davis S. Taga T. Li Y. Birren S.J. Yasukawa K. Kishimoto T. Anderson D.J. Stahl N. Yancopoulos G.D. Cell. 1992; 69: 1121-1132Abstract Full Text PDF PubMed Scopus (610) Google Scholar, 6Yin T. Taga T. Tsang M. L-S. Yasukawa K. Kishimoto T. Yang Y-C. J. Immunol. 1993; 151: 2555-2561PubMed Google Scholar, 7Hilton D.J. Hilton A.A. Raicevic A. Rakar S. Harrison-Smith M. Gough N.M. Begley C.G. Metcalf D. Nicola N.A. Willson T.A. EMBO J. 1994; 13: 4765-4775Crossref PubMed Scopus (253) Google Scholar, 8Davis S. Aldrich T.H. Stahl N. Pan L. Taga T. Kishimoto T. Ip N.Y. Yancopoulous G.D. Science. 1993; 260: 1805-1808Crossref PubMed Scopus (592) Google Scholar, 9Hirano T. Matsuda T. Nakajima K. Stem Cells. 1994; 12: 262-277Crossref PubMed Scopus (165) Google Scholar). This IL-6 family of cytokines plays roles in the immune response, hematopoiesis, inflammation, and nervous system activity (9Hirano T. Matsuda T. Nakajima K. Stem Cells. 1994; 12: 262-277Crossref PubMed Scopus (165) Google Scholar). Furthermore, signals are at least in part generated through gp130 upon stimulation with the IL-6 family of cytokines. Therefore, clarification of the molecular mechanisms of signal transduction through gp130 is essential to understand the action of the IL-6 family of cytokines in a wide range of tissues and organs, including the immune and nervous systems. interleukin IL-6 receptor soluble human IL-6 receptor α granulocyte macrophage colony-stimulating factor Polyacrylamide gel electrophoresis. Stimulation of the receptors by the IL-6 family of cytokines results in a rapid tyrosine phosphorylation of multiple molecules, including gp130 itself (10Murakami M. Narazaki M. Hibi M. Yawata H. Yasukawa K. Hamaguchi M. Taga T. Kishimoto T. Proc. Natl. Acad. Sci. U. S. A. 1991; 99: 11349-11353Crossref Scopus (489) Google Scholar, 11Matsuda T. Yamanaka Y. Hirano T. Biochem. Biophys. Res. Commun. 1994; 200: 821-828Crossref PubMed Scopus (37) Google Scholar), although the cytoplasmic region of gp130 lacks an intrinsic tyrosine kinase domain like that of other cytokine receptors (2Hibi M. Murakami M. Saito M. Hirano T. Taga T. Kishimoto T. Cell. 1990; 63: 1149-1157Abstract Full Text PDF PubMed Scopus (1097) Google Scholar). Therefore, the identification of the tyrosine kinases involved in gp130-mediated signal transduction is one of the central issues in the field of cytokine research. Recently, it was shown that Janus kinase (Jak) family kinases, which are expressed in a wide range of tissues and cells, are activated by the IL-6 family of cytokines (11Matsuda T. Yamanaka Y. Hirano T. Biochem. Biophys. Res. Commun. 1994; 200: 821-828Crossref PubMed Scopus (37) Google Scholar, 12Lutticken 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. 1993; 263: 89-92Crossref Scopus (708) Google Scholar, 13Stahl N. Boulton T.G. Farruggella T. Ip N.Y. Davis S. Witthuhn B.A. Quelle F.W. Silvennoinen O. Barbieri G. Pellgrini S. Ihle J.N. Yancopoulos G.D. Science. 1993; 263: 92-95Crossref Scopus (847) Google Scholar, 14Berger L.C. Hawley T.S. Lust J.A. Goldman S.J. Hawley R.G. Biochem. Biophys. Res. Commun. 1994; 202: 596-605Crossref PubMed Scopus (47) Google Scholar, 15Narazaki M. Witthuhn B.A. Yoshida K. Silvennoinen O. Yasukawa K. Ihle J.N. Kishimoto T. Taga T. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 2285-2289Crossref PubMed Scopus (254) Google Scholar), leading to the tyrosine phosphorylation and activation of Stat family transcription factors (12Lutticken 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. 1993; 263: 89-92Crossref Scopus (708) Google Scholar, 16Matsuda T. Hirano T. Blood. 1994; 83: 3457-3461Crossref PubMed Google Scholar, 17Fujitani Y. Nakajima K. Kojima H. Nakae K. Takeda T. Hirano T. Biochem. Biophys. Res. Commun. 1994; 202: 1181-1187Crossref PubMed Scopus (56) Google Scholar). We also showed that IL-6 induced the tyrosine phosphorylation and activation of a Stat-associated novel tyrosine kinase, Sak (or p72sak) (16Matsuda T. Hirano T. Blood. 1994; 83: 3457-3461Crossref PubMed Google Scholar). Furthermore, we demonstrated that the stimulation of gp130 in a pro-B cell line results in the activation of both Btk and Tec tyrosine kinases and that both kinases associate with gp130 independently of ligand stimulation (18Matsuda T. Takahashi-Tezuka M. Fukada T. Okuyama Y. Fujitani Y. Tsukada S. Mano H. Hirai H. Witte O.N. Hirano T. Blood. 1995; 84: 627-633Crossref Google Scholar). Btk tyrosine kinase was identified as the gene product responsible for X-linked agammaglobulinemia (XLA) in humans (19Tsukada S. Saffran D.C. Rawlings D.J. Parolini O. Allen R.C. Klisak I. Sparkes R.S. Kubagawa H. Mohandas T. Quan S. Belmont J.W. Cooper M.D. Conley M.E. Witte O.N. Cell. 1993; 72: 279-290Abstract Full Text PDF PubMed Scopus (1153) Google Scholar, 20Vetrie D. Vorechovsky I. Sideras P. Holland J. Davies A. Flinter F. Hammarstrom L. Kinnon C. Levinsky R. Bobrow M. Smith C.I.M. Bentley D.R. Nature. 1993; 361: 226-233Crossref PubMed Scopus (1249) Google Scholar) and X-linked immunodeficiency (XID) in mice (21Rawlings D.J. Saffran D.C. Tsukada S. Largaespada D.A. Grimaldi J.C. Cohen L. Mohr R.N. Bazan J.F. Howard M. Copeland N.G. Jenkins N.A. Witte O.N. Science. 1993; 358: 358-361Crossref Scopus (777) Google Scholar, 22Thomas J.D. Sideras P. Smith C.I.M. Vorechovsky I. Chapman V. Paul W.E. Science. 1993; 261: 355-358Crossref PubMed Scopus (572) Google Scholar), showing that Btk plays a central role in β cell signaling events. Tec is abundantly expressed in hematopoietic lineage cells (23Mano H. Mano K. Tang B. Koehler M. Yi T. Gilbert D.J. Jenkins N.A. Copeland N.G. Ihle J.N. Oncogene. 1993; 8: 417-424PubMed Google Scholar) and is thought to be involved in the mitogenic signaling pathway of both IL-3 and stem cell factor (24Mano H. Yamashita Y. Sato K. Yazaki Y. Hirai H. Blood. 1995; 85: 343-350Crossref PubMed Google Scholar, 25Tang B. Mano H. Yi T. Ihle J.N. Mol. Cell. Biol. 1994; 14: 8432-8437Crossref PubMed Scopus (88) Google Scholar). Because both Btk and Tec are mainly expressed in lymphohematopoietic lineage cells and the action of gp130 is not limited to these lineage cells, one may expect the presence of other tyrosine kinases, the expression patterns of which are different from those of Btk, Tec, or Jak. c-fes/fps proto-oncogene encodes a 92-kDa nonreceptor-type protein tyrosine kinase that is mainly expressed in hematopoietic cells (26Feldman R.A. Gabrilove J.L. Tam J.P. Moore M.A.S. Hanafusa H. Proc. Natl. Acad. Sci. U. S. A. 1985; 82: 2379-2383Crossref PubMed Scopus (109) Google Scholar, 27MacDonald I. Levy J. Pawson T. Mol. Cell. Biol. 1985; 5: 2543-2551Crossref PubMed Scopus (96) Google Scholar). However, c-fes/fps was recently shown to be expressed in cardiac muscle and the nervous system (28Care A. Mattia G. Montesoro E. Parolini I. Russo G. Colombo M.P. Peschle C. Oncogene. 1994; 9: 739-747PubMed Google Scholar). Because gp130 is also expressed in the heart and brain (29Saito M. Yoshida K. Hibi M. Taga T. Kishimoto T. J. Immunol. 1992; 148: 4066-4071PubMed Google Scholar), we examined whether gp130 stimulation activates Fes tyrosine kinase. In this study, we showed that the stimulation of gp130 in murine hematopoietic cells induced the activation of Fes kinase and that Fes associated with gp130 independently of ligand stimulation. Cell Lines—An IL-3-dependent murine pro B-cell line, BAF-B03, was maintained in RPMI 1640 medium supplemented with 10% fetal calf serum and 10% conditioned medium from WEHI-3B cells as a source of IL-3. A stable transfectant that expresses murine gp130, BAFm130, was established by transfecting BAF-B03 with pBCMGm130 as described previously (11Matsuda T. Yamanaka Y. Hirano T. Biochem. Biophys. Res. Commun. 1994; 200: 821-828Crossref PubMed Scopus (37) Google Scholar) and maintained in the above mentioned medium in the presence of 1 mg/ml G418. A murine hematopoietic cell line, Y6 (30Oritani K. Kaisho T. Nakajima K. Hirano T. Blood. 1992; 80: 2298-2305Crossref PubMed Google Scholar), was maintained in RPMI 1640 medium supplemented with 10% fetal calf serum. Antibodies—Monoclonal antibodies against human gp130 (AM64) and murine gp130 (HMβ1 and RMβ3 (HMβ1 and RMβ3,4)) were previously described (2Hibi M. Murakami M. Saito M. Hirano T. Taga T. Kishimoto T. Cell. 1990; 63: 1149-1157Abstract Full Text PDF PubMed Scopus (1097) Google Scholar, 31Matsuda T. Hirano T. Biochem. Biophys. Res. Commun. 1994; 202: 637-642Crossref PubMed Scopus (8) Google Scholar). Rabbit anti-Fes antiserum was generated against a synthetic peptide corresponding to amino acid residues 424–443 of p92c-fes, an upstream region of the SH2 domain, and used for immunoprecipitation (32Hanazono Y. Chiba S. Sasaki K. Mano H. Miyajima A. Arai K. Yazaki Y. Hirai H. EMBO J. 1993; 12: 1641-1646Crossref PubMed Scopus (144) Google Scholar). F115 antibody is a rat monoclonal anti-p92c-fes antibody purchased from Oncogene Science (Manhasset, NY) and used for Western blotting. We also made rabbit anti-Fes antiserum against a synthetic peptide corresponding to the C-terminal 15 amino acid residues of murine p92c-fes (termed anti-Fes/C) and used it for both immunoprecipitation and Western blotting. Immunoprecipitation and Immunoblotting—Y6 cells were starved in serum-free medium for 1–2 h and then incubated for various periods with recombinant IL-6 (200 ng/ml, kindly provided from Ajinomoto Co., Kawasaki, Kanagawa, Japan). Other cells were starved in serum-free medium for 1–2 h and then incubated for various times with recombinant IL-6 (200 ng/ml) and recombinant soluble human IL-6 receptor α (sIL-6Rα) (33Yasukawa K. Saito T. Fukunaga T. Sakimori Y. Koishihara Y. Fukui H. Ohsugi Y. Matsuda T. Yawata H. Hirano T. Taga T. Kishimoto T. J. Biochem. (Tokyo). 1990; 108: 673-676Crossref PubMed Scopus (144) Google Scholar). The cells were lysed in a lysis buffer (50 mm Tris-HCl, pH 7.4, 0.15 m NaCl, containing 1% Nonidet P-40, 1 mm sodium orthovanadate, 1 mm NaF, 1 mm phenylmethylsulfonyl fluoride, and 10 μg/ml each of aprotinin, pepstatin, and leupeptin). In some experiments, cells were lysed under a mild detergent condition utilizing a lysis buffer containing 0.1% Nonidet P-40. The immunoprecipitates from the cell lysates were resolved to 4–20% SDS-PAGE and transferred to an Immobilon filter (Millipore, Bedford, MA). The Immobilon filter was then immunoblotted with an anti-phosphotyrosine antibody (4G10, UBI, New YorK, NY). Immunoreactive proteins were visualized using an enhanced chemiluminescence detection system (Amersham, Tokyo, Japan). In-gel Kinase Assay—An in-gel kinase assay was performed as described previously (16Matsuda T. Hirano T. Blood. 1994; 83: 3457-3461Crossref PubMed Google Scholar). The immunoprecipitate with anti-Fes antiserum from cell lysates was resolved by 4–20% SDS-PAGE. After electrophoresis, the gel was washed twice with 50 mm Tris-HCl, pH 7.4, and 5 mm 2-mercaptoethanol, incubated with 50 mm Tris-HCl, pH 7.4, 5 mm 2-mercaptoethanol, and 6 m guanidine hydrochloride and washed with 50 mm Tris-HCl, pH 7.4 and 5 mm 2-mercaptoethanol containing 0.04% Tween 40 (Nacalai Tesque, Kyoto, Japan). The gel was incubated in 20 mm HEPES, pH 7.4, 20 mm MgCl2, 20 mm MnCl2, 2 mm dithiothreitol and 5 μCi/ml [γ-32P]αTP at 30 °C for 30 min. Finally, the gel was washed several times with 5% trichloroacetic acid and 5% sodium pyrophosphate; this step was followed by drying and autoradiography. Phosphorylated proteins were detected by a Fujix BAS2000 Bio-image analyzer (Fuji Film, Tokyo, Japan). Since the complex of IL-6 and sIL-6Rα can stimulate gp130 (2Hibi M. Murakami M. Saito M. Hirano T. Taga T. Kishimoto T. Cell. 1990; 63: 1149-1157Abstract Full Text PDF PubMed Scopus (1097) Google Scholar, 9Hirano T. Matsuda T. Nakajima K. Stem Cells. 1994; 12: 262-277Crossref PubMed Scopus (165) Google Scholar), to examine the signal transduction pathway through gp130 we stimulated a BAF-B03 transformant that expresses gp130, BAFm130, with IL-6 and sIL-6Rα. Fig. 1 shows that gp130 stimulation induced tyrosine phosphorylation of Fes in BAFm130. We also showed that IL-6 induced tyrosine phosphorylation of Fes protein in a murine hematopoietic cell line, Y6, which differentiates into macrophages with apoptotic cell death upon IL-6 stimulation (Fig. 1, a, 2). Reprobing with antisera against respective proteins confirmed that the stimulation-induced changes were not due to alteration of protein levels (Fig. 1, lower panels). The time course of tyrosine phosphorylation of Fes by gp130 stimulation was investigated in BAFm130 cells. As shown in Fig. 1b, tyrosine phosphorylation of Fes reached the maximum level 5–15 min after gp130 stimulation and decreased after 30 min. We further examined whether gp130 stimulation actually activates the tyrosine kinase activity of Fes. Cell lysates of BAFm130 were immunoprecipitated with anti-Fes antiserum, and the kinase activity of the immunoprecipitate was examined by an in-gel kinase assay. Fig. 1c shows that the immunoprecipitate from the cells stimulated by gp130 had higher in vitro kinase activity than that of unstimulated cells at the position corresponding to the molecular weight of Fes proteins, indicating that the gp130 stimulation actually activated Fes tyrosine kinase. Next, we tried to determine whether Fes tyrosine kinase associates with gp130. For this purpose, we made another anti-Fes antiserum, anti-Fes/C, to raise the sensitivity of the detection of Fes protein. We immunoprecipitated the cell lysates of BAFm130 under a mild detergent condition as described under “Materials and Methods.” Fig. 2a shows that the immunoprecipitate with an anti-murine gp130 monoclonal antibody from either gp130-stimulated or unstimulated BAFm130 cells contained Fes, indicating that Fes is associated with gp130 independently of ligand stimulation. To further confirm this, we examined whether the immunoprecipitate with anti-Fes contains gp130. Fig. 2b shows that gp130 was present in the immunoprecipitate with anti-Fes antiserum from either stimulated or unstimulated cells. Taken together the results showed that Fes protein was constitutively associated with gp130. c-fes/fps proto-oncogene encodes a 92-kDa nonreceptor type protein tyrosine kinase consisting of a unique N-terminal domain, a central SH2 domain, and a C-terminal catalytic domain. The expression of Fes/Fps has been reported exclusively in hematopoietic cells and most abundantly in those of the myeloid lineages (26Feldman R.A. Gabrilove J.L. Tam J.P. Moore M.A.S. Hanafusa H. Proc. Natl. Acad. Sci. U. S. A. 1985; 82: 2379-2383Crossref PubMed Scopus (109) Google Scholar, 27MacDonald I. Levy J. Pawson T. Mol. Cell. Biol. 1985; 5: 2543-2551Crossref PubMed Scopus (96) Google Scholar). In embryonic and adult hematopoietic cells, Fes is abundantly expressed in both undifferentiated progenitors and differentiated granulomonocytic precursors but not in erythroblasts. It has been shown that IL-4, GM-CSF, and erythropoietin induce the tyrosine phosphorylation and activation of Fes tyrosine kinase (32Hanazono Y. Chiba S. Sasaki K. Mano H. Miyajima A. Arai K. Yazaki Y. Hirai H. EMBO J. 1993; 12: 1641-1646Crossref PubMed Scopus (144) Google Scholar, 34Hanazono Y. Chiba S. Sasaki K. Mano H. Yazaki Y. Hirai H. Blood. 1993; 81: 3193-3196Crossref PubMed Google Scholar, 35Izuhara K. Feldman R.A. Greer P. Harada N. J. Biol. Chem. 1994; 269: 18623-18629Abstract Full Text PDF PubMed Google Scholar). Furthermore, Fes protein physically associates with either IL-4 receptor or the β chain of GM-CSF receptor. In this study, we showed that Fes was also involved in the gp130-mediated signaling pathway. Since the IL-6 family of cytokines is known to act on hematopoietic lineage cells (9Hirano T. Matsuda T. Nakajima K. Stem Cells. 1994; 12: 262-277Crossref PubMed Scopus (165) Google Scholar, 36Ogawa M. Blood. 1993; 81: 2844-2853Crossref PubMed Google Scholar), all evidence shows that Fes tyrosine kinase is a molecule commonly involved in signal transduction through hematopoietic cytokine receptors. By in situ hybridization analysis of c-fes expression, a spatially and temporally regulated transcription of c-fes has been shown in the central nervous system and in developing cartilage (28Care A. Mattia G. Montesoro E. Parolini I. Russo G. Colombo M.P. Peschle C. Oncogene. 1994; 9: 739-747PubMed Google Scholar). Furthermore, c-fes expression has been detected in cardiac muscle in early human embryos. More interestingly, transgenic mice carrying the v-fps/fes tyrosine kinase gene showed several independent abnormalities such as cardiomegaly and striking bilateral enlargement of the trigeminal nerves, suggesting that the v-fps/fes transgene is involved in mammalian neural and cardiac development (37Yee S-P. Mock D. Maltby V. Silver M. Rossant J. Bernstein A. Pawson T. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 5873-5877Crossref PubMed Scopus (30) Google Scholar). Considering the wide expression of c-fes and the pleiotropic effects of v-fps transgene, c-fes may play a role in the ontogenic development of nonhematopoietic tissues including the central nervous system and heart. Recently, the cDNA cloning of a novel cytokine that induces cardiac myocyte hypertrophy, cardiotropin-1, was performed (38Pennica D. King K.L. Shaw J.J. Luis E. Rullamas J. Luoh S.-M. Darbonne W.C. Knutzon D.S. Yen R. Chien K.R. Barker J.B. Wood W.I. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 1142-1146Crossref PubMed Scopus (500) Google Scholar). This novel cytokine is similar to IL-6 and seems to utilize gp130 as its receptor subunit. Since gp130 is shared by the receptors for both ciliary neurotrophic factor and leukemia inhibitory factor, which act on nerve cells (9Hirano T. Matsuda T. Nakajima K. Stem Cells. 1994; 12: 262-277Crossref PubMed Scopus (165) Google Scholar), and gp130 is expressed not only in hematopoietic lineage cells but also in nerve cells and the heart (29Saito M. Yoshida K. Hibi M. Taga T. Kishimoto T. J. Immunol. 1992; 148: 4066-4071PubMed Google Scholar), it is suggested that Fes tyrosine kinase plays a role in signal transduction through gp130 not only in the hematopoietic system as shown in the present study but also in the nervous system and heart. Although Jak tyrosine kinase is a tyrosine kinase that associates with many cytokine receptors, the pleiotropic functions of cytokine may be generated by the involvement of additional receptor-associated nonreceptor type tyrosine kinases such as Fes, Btk, and Tec or a combination of these tyrosine kinases, which are expressed differently in a variety of tissues." @default.
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• W2065522904 title "Activation of Fes Tyrosine Kinase by gp130, an Interleukin-6 Family Cytokine Signal Transducer, and Their Association" @default.
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