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• W2009650205 abstract "Activation of p70 S6 kinase (p70S6K) by growth factors requires multiple signal inputs involving phosphoinositide 3-kinase (PI3K), its effector Akt, and an unidentified kinase that phosphorylates Ser/Thr residues (Ser411, Ser418, Ser424, and Thr421) clustered at its autoinhibitory domain. However, the mechanism by which G protein-coupled receptors activate p70S6K remains largely uncertain. By using vascular smooth muscle cells in which we have demonstrated Ras/extracellular signal-regulated kinase (ERK) activation through Ca2+-dependent, epidermal growth factor (EGF) receptor transactivation by Gq-coupled angiotensin II (Ang II) receptor, we present a unique cross-talk required for Ser411 phosphorylation of p70S6K by Ang II. Both p70S6K Ser411 and Akt Ser473phosphorylation by Ang II appear to involve EGF receptor transactivation and were inhibited by dominant-negative Ras, whereas the phosphorylation of p70S6K and ERK but not Akt was sensitive to the MEK inhibitor. By contrast, the phosphorylation of p70S6K and Akt but not ERK was sensitive to PI3K inhibitors. Similar inhibitory pattern on these phosphorylation sites by EGF but not insulin was observed. Taken together with the inhibition of Ang II-induced p70S6K activation by dominant-negative Ras and the MEK inhibitor, we conclude that Ang II-initiated activation of p70S6K requires both ERK cascade and PI3K/Akt cascade that bifurcate at the point of EGF receptor-dependent Ras activation. Activation of p70 S6 kinase (p70S6K) by growth factors requires multiple signal inputs involving phosphoinositide 3-kinase (PI3K), its effector Akt, and an unidentified kinase that phosphorylates Ser/Thr residues (Ser411, Ser418, Ser424, and Thr421) clustered at its autoinhibitory domain. However, the mechanism by which G protein-coupled receptors activate p70S6K remains largely uncertain. By using vascular smooth muscle cells in which we have demonstrated Ras/extracellular signal-regulated kinase (ERK) activation through Ca2+-dependent, epidermal growth factor (EGF) receptor transactivation by Gq-coupled angiotensin II (Ang II) receptor, we present a unique cross-talk required for Ser411 phosphorylation of p70S6K by Ang II. Both p70S6K Ser411 and Akt Ser473phosphorylation by Ang II appear to involve EGF receptor transactivation and were inhibited by dominant-negative Ras, whereas the phosphorylation of p70S6K and ERK but not Akt was sensitive to the MEK inhibitor. By contrast, the phosphorylation of p70S6K and Akt but not ERK was sensitive to PI3K inhibitors. Similar inhibitory pattern on these phosphorylation sites by EGF but not insulin was observed. Taken together with the inhibition of Ang II-induced p70S6K activation by dominant-negative Ras and the MEK inhibitor, we conclude that Ang II-initiated activation of p70S6K requires both ERK cascade and PI3K/Akt cascade that bifurcate at the point of EGF receptor-dependent Ras activation. phosphoinositide 3-kinase extracellular signal-regulated kinase angiotensin II angiotensin II type-1 receptor G protein-coupled receptor epidermal growth factor EGF receptor platelet-derived growth factor PDGF receptor vascular smooth muscle cells protein kinase B mitogen-activated protein kinase protein kinase C 1,2-bis(O-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetra(acetoxymethyl)ester Dulbecco's modified Eagle's medium 4-morpholinepropanesulfonic acid Chinese hamster ovary c-Jun N-terminal kinase The ubiquitous mitogen-activated Ser/Thr kinase, p70 ribosomal protein S6 kinase (p70S6K) participates in the translation of mRNAs, which contain an oligopyrimidine tract at their transcriptional start site. This family of mRNAs encode many of the components of the translational apparatus, including ribosomal proteins and elongation factors. Thus, activation of p70S6K has long been thought to be a prerequisite to protein synthesis. Inhibition of the kinase activation suppresses cell growth and in some cell types blocks cell cycle progression (1Chou M.M. Blenis J. Curr. Opin. Cell Biol. 1995; 7: 806-814Crossref PubMed Scopus (245) Google Scholar, 2Pullen N. Thomas G. FEBS Lett. 1997; 410: 78-82Crossref PubMed Scopus (483) Google Scholar, 3Avruch J. Mol. Cell. Biochem. 1998; 182: 31-48Crossref PubMed Scopus (321) Google Scholar).Activation of p70S6K appears to involve multiple signal inputs. The immunosuppressant rapamycin is the most potent inhibitor of p70S6K described, blocking its activation by all known agents (1Chou M.M. Blenis J. Curr. Opin. Cell Biol. 1995; 7: 806-814Crossref PubMed Scopus (245) Google Scholar). It forms a gain-of-function inhibitory complex with FKBP12 that targets mTOR, a member of the phosphatidylinositol 3-kinase (PI3K)1-related family of protein kinases (4Thomas G. Hall M.N. Curr. Opin. Cell Biol. 1997; 9: 782-787Crossref PubMed Scopus (411) Google Scholar). Because an mTOR mutant, which is unable to bind rapamycin-FKBP12, protects p70S6K activity in the presence of the inhibitor, it has been reasoned that mTOR is an upstream regulator of p70S6K (5Brown E.J. Beal P.A. Keith C.T. Chen J. Shin T.B. Schreiber S.L. Nature. 1995; 377: 441-446Crossref PubMed Scopus (616) Google Scholar). PI3K has also been implicated in the signal transduction of p70S6K activation (6Chung J. Grammer T.C. Lemon K.P. Kazlauskas A. Blenis J. Nature. 1994; 370: 71-75Crossref PubMed Scopus (656) Google Scholar). Constitutively active PI3K alleles cause elevations in p70S6K activity, and the inhibitors of PI3K, wortmannin and LY294002, inhibit the activation of p70S6K by various agonists (1Chou M.M. Blenis J. Curr. Opin. Cell Biol. 1995; 7: 806-814Crossref PubMed Scopus (245) Google Scholar, 2Pullen N. Thomas G. FEBS Lett. 1997; 410: 78-82Crossref PubMed Scopus (483) Google Scholar, 3Avruch J. Mol. Cell. Biochem. 1998; 182: 31-48Crossref PubMed Scopus (321) Google Scholar). The downstream effector of PI3K, Akt/ protein kinase B (PKB) mediates PI3K-dependent p70S6Kactivation. Oncogenic or membrane-targeted mutants of Akt activate p70S6K, which is blocked by rapamycin (7Burgering B.M. Coffer P.J. Nature. 1995; 376: 599-602Crossref PubMed Scopus (1872) Google Scholar, 8Kohn A.D. Takeuchi F. Roth R.A. J. Biol. Chem. 1996; 271: 21920-21926Abstract Full Text Full Text PDF PubMed Scopus (407) Google Scholar). Recently, phosphorylation and activation of mTOR by Akt was reported (9Scott P.H. Brunn G.J. Kohn A.D. Roth R.A. Lawrence J.J. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 7772-7777Crossref PubMed Scopus (408) Google Scholar).Although mitogens that activate p70S6K simultaneously activate extracellular signal-regulated kinase (ERK/MAPK), p70S6K and the Ras/ERK cascade have since been shown to lie on distinct pathways (6Chung J. Grammer T.C. Lemon K.P. Kazlauskas A. Blenis J. Nature. 1994; 370: 71-75Crossref PubMed Scopus (656) Google Scholar, 10Ballou L.M. Luther H. Thomas G. Nature. 1991; 349: 348-350Crossref PubMed Scopus (152) Google Scholar, 11Ming X.F. Burgering B.M. Wennstrom S. Claesson W.L. Heldin C.H. Bos J.L. Kozma S.C. Thomas G. Nature. 1994; 371: 426-429Crossref PubMed Scopus (204) Google Scholar, 12Sakaue M. Bowtell D. Kasuga M. Mol. Cell. Biol. 1995; 15: 379-388Crossref PubMed Scopus (60) Google Scholar). Rapamycin inactivates p70S6K without having any discernible effects on ERK (6Chung J. Grammer T.C. Lemon K.P. Kazlauskas A. Blenis J. Nature. 1994; 370: 71-75Crossref PubMed Scopus (656) Google Scholar). A Ras mutant blocks activation of ERK but not p70S6K. Certain PDGF receptor mutants, which normally activate Ras, fail to activate p70S6K (11Ming X.F. Burgering B.M. Wennstrom S. Claesson W.L. Heldin C.H. Bos J.L. Kozma S.C. Thomas G. Nature. 1994; 371: 426-429Crossref PubMed Scopus (204) Google Scholar). However, a recent study showed that a conditionally active Raf-1 mutant as well as a constitutively active MEK1 activates p70S6K in CCL39 fibroblasts (13Lenormand P. McMahon M. Pouyssegur J. J. Biol. Chem. 1996; 271: 15762-15768Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar). Beside the ERK cascade, the small G proteins, Cdc42 and Rac1 (14Chou M.M. Blenis J. Cell. 1996; 85: 573-583Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar), and both conventional (6Chung J. Grammer T.C. Lemon K.P. Kazlauskas A. Blenis J. Nature. 1994; 370: 71-75Crossref PubMed Scopus (656) Google Scholar) and atypical (15Akimoto K. Nakaya M. Yamanaka T. Tanaka J. Matsuda S. Weng Q.P. Avruch J. Ohno S. Biochem. J. 1998; 335: 417-424Crossref PubMed Scopus (67) Google Scholar) PKCs are also implicated in p70S6K activation.Along with the diversity in the activating pathways, a complex multisite phosphorylation, directed to different domains, are required for p70S6K activation (2Pullen N. Thomas G. FEBS Lett. 1997; 410: 78-82Crossref PubMed Scopus (483) Google Scholar, 3Avruch J. Mol. Cell. Biochem. 1998; 182: 31-48Crossref PubMed Scopus (321) Google Scholar). Phosphorylation of closely clustered Ser411, Ser418, Thr421, and Ser424, located within a pseudosubstrate autoinhibitory domain, is not sufficient for the kinase activation but seems to be a prerequisite for its activation (2Pullen N. Thomas G. FEBS Lett. 1997; 410: 78-82Crossref PubMed Scopus (483) Google Scholar, 3Avruch J. Mol. Cell. Biochem. 1998; 182: 31-48Crossref PubMed Scopus (321) Google Scholar). Although each of these Ser/Thr residues are followed immediately by a proline residue and can be phosphorylated in vitro by an array of proline-directed kinases including ERK (16Mukhopadhyay N.K. Price D.J. Kyriakis J.M. Pelech S. Sanghera J. Avruch J. J. Biol. Chem. 1992; 267: 3325-3335Abstract Full Text PDF PubMed Google Scholar), in vivo requirement of these kinases has not been substantiated to date. The phosphorylation of Thr229 in the catalytic domain and Thr389 in the linker domain is stimulated by PI3K is inhibited by wortmannin and appears to be essential for the kinase activation (2Pullen N. Thomas G. FEBS Lett. 1997; 410: 78-82Crossref PubMed Scopus (483) Google Scholar, 3Avruch J. Mol. Cell. Biochem. 1998; 182: 31-48Crossref PubMed Scopus (321) Google Scholar). These sites are conserved in many members of Ser/Thr kinases including PKC and Akt/PKB. Recently, the phosphoinositide-dependent protein kinase PDK1, which was originally identified as a Thr308kinase for Akt/PKB, has also been shown to phosphorylate the homologous site in p70S6K, Thr229 (17Pullen N. Dennis P.B. Andjelkovic M. Dufner A. Kozma S.C. Hemmings B.A. Thomas G. Science. 1998; 279: 707-710Crossref PubMed Scopus (723) Google Scholar, 18Alessi D.R. Kozlowski M.T. Weng Q.P. Morrice N. Avruch J. Curr. Biol. 1998; 8: 69-81Abstract Full Text Full Text PDF PubMed Scopus (512) Google Scholar), thus connecting a link between PI3K and p70S6K. Alternatively,in vitro phosphorylation of the Thr389 by mTOR has recently been demonstrated (19Burnett P.E. Barrow R.K. Cohen N.A. Snyder S.H. Sabatini D.M. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 1432-1437Crossref PubMed Scopus (924) Google Scholar). Taken together, it now appears likely that p70S6K activation requires a complex array of separate, concurrent phosphorylations at multiple sites catalyzed by several protein kinases. However, the precise mechanism of activation as well as the identity of the p70S6K kinases are yet largely unclear.Recently, rapid activation of p70S6K has been reported in rat balloon-injured arteries (20Koyama H. Olson N.E. Dastvan F.F. Reidy M.A. Circ. Res. 1998; 82: 713-721Crossref PubMed Scopus (122) Google Scholar) and pressure-overloaded hearts (21Laser M. Kasi V.S. Hamawaki M. Cooper G. Kerr C.M. Kuppuswamy D. J. Biol. Chem. 1998; 273: 24610-24619Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar), suggesting the significance of p70S6K as a potential therapeutic target in cardiovascular diseases. Angiotensin II (Ang II), a major effector peptide of the renin-angiotensin system, is now widely believed to play a critical role in vascular remodeling associated with hypertension, atherosclerosis, and restenosis after vascular injury (22Timmermans P.B.M.W.M. Wong P.C. Chiu A.T. Herblin W.F. Benfield P. Carini D.J. Lee R.J. Wexler R.R. Saye J.A.M. Smith R.D. Pharmacol. Rev. 1993; 45: 205-251PubMed Google Scholar). We and others have previously cloned the Ang II type 1 receptor (AT1), a heterotrimeric G protein-coupled receptor (GPCR) (23Sasaki K. Yamano Y. Bardhan S. Iwai N. Murray J.J. Hasegawa M. Matsuda Y. Inagami T. Nature. 1991; 351: 230-233Crossref PubMed Scopus (773) Google Scholar, 24Murphy T.J. Alexander R.W. Griendling K.K. Runge M.S. Bernstein K.E. Nature. 1991; 351: 233-236Crossref PubMed Scopus (1166) Google Scholar) that not only mediates diverse hemodynamic effects of Ang II but also promotes hypertrophy and/or hyperplasia of vascular smooth muscle cells (VSMC) (25Griendling K.K. Ushio-Fukai M. Lassegue B. Alexander R.W. Hypertension. 1997; 29: 366-373Crossref PubMed Google Scholar, 26Berk B.C. J. Am. Soc. Nephrol. 1999; 10: S62-S68Crossref PubMed Google Scholar). In VSMC, Gq-coupled AT1 activates phospholipase C, which initiates the generation of inositol trisphosphate and diacylglycerol, causing intracellular Ca2+ mobilization and PKC activation, respectively (25Griendling K.K. Ushio-Fukai M. Lassegue B. Alexander R.W. Hypertension. 1997; 29: 366-373Crossref PubMed Google Scholar). Moreover, Ang II induces several signaling events commonly evoked by growth factor receptors, such as protein tyrosine phosphorylation and activation of ERK in VSMC (25Griendling K.K. Ushio-Fukai M. Lassegue B. Alexander R.W. Hypertension. 1997; 29: 366-373Crossref PubMed Google Scholar, 26Berk B.C. J. Am. Soc. Nephrol. 1999; 10: S62-S68Crossref PubMed Google Scholar, 27Inagami T. Eguchi S. Numaguchi K. Motley E.D. Tang H. Matsumoto T. Yamakawa T. J. Am. Soc. Nephrol. 1999; 10: S57-S61PubMed Google Scholar). Earlier studies from our laboratory indicate that a Ca2+-dependent tyrosine kinase may mediate Ang II-induced Ras and ERK activation in cultured VSMC (28Eguchi S. Matsumoto T. Motley E.D. Utsunomiya H. Inagami T. J. Biol. Chem. 1996; 271: 14169-14175Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar). Subsequently, we have shown that this mechanism involves the ligand-independent transactivation of the EGF receptor (EGFR) (29Eguchi S. Numaguchi K. Iwasaki H. Matsumoto T. Yamakawa T. Utsunomiya H. Motley E.D. Kawakatsu H. Owada K.M. Hirata Y. Marumo F. Inagami T. J. Biol. Chem. 1998; 273: 8890-8896Abstract Full Text Full Text PDF PubMed Scopus (503) Google Scholar).Previous studies demonstrated that Ang II stimulated p70S6Kthrough AT1 in cultured VSMC and cardiac myocytes and that rapamycin markedly inhibited Ang II-induced protein synthesis in these cells (30Giasson E. Meloche S. J. Biol. Chem. 1995; 270: 5225-5231Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 31Sadoshima J. Izumo S. Circ. Res. 1995; 77: 1040-1052Crossref PubMed Scopus (183) Google Scholar). Although much progress has recently been achieved to understand the signaling relay from GPCRs to the ERK cascade (32Gutkind J.S. J. Biol. Chem. 1998; 273: 1839-1842Abstract Full Text Full Text PDF PubMed Scopus (689) Google Scholar), little is known about the mechanism by which GPCRs activate p70S6K (33Wilson M. Burt A.R. Milligan G. Anderson N.G. J. Biol. Chem. 1996; 271: 8537-8540Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar). Because both ERK and p70S6K have been implicated in Ang II-induced protein synthesis (30Giasson E. Meloche S. J. Biol. Chem. 1995; 270: 5225-5231Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar, 34Servant M.J. Giasson E. Meloche S. J. Biol. Chem. 1996; 271: 16047-16052Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar, 35Eguchi S. Iwasaki H. Hirata Y. Frank J.D. Motley E.D. Yamakawa T. Numaguchi K. Inagami T. Eur. J. Pharmacol. 1999; 376: 203-206Crossref PubMed Scopus (43) Google Scholar) and an unidentified proline-directed protein kinase such as ERK may be a required link leading to p70S6K activation through Ser/Thr phosphorylation at its pseudosubstrate domain, the present study was designed to examine possible cross-talk between the ERK cascade and the Ser411 phosphorylation of p70S6K in Ang II-stimulated VSMC. Here, we have presented several lines of evidence indicating that Ang II-induced p70S6K activation requires not only the PI3K/Akt cascade but also the ERK cascade, both of which exist downstream of the Ca2+-dependent EGFR transactivation and bifurcates at the level of Ras.DISCUSSIONThe major finding of this study is that Ang II-induced p70S6K activation in VSMC requires two parallel pathways that bifurcate at the point of EGFR-dependent Ras activation. One is the ERK cascade and the other may involve PI3K/Akt/mTOR. These data will provide new insight into the signaling mechanism by which Ang II contributes vascular hypertrophy.Although phosphorylation of the autoinhibitory domain of p70S6K is not sufficient for the kinase activation, recent studies have shown its ability to gain access of p70S6Kkinases such as PDK1 to sites whose phosphorylation are critical for p70S6K activation (2Pullen N. Thomas G. FEBS Lett. 1997; 410: 78-82Crossref PubMed Scopus (483) Google Scholar, 17Pullen N. Dennis P.B. Andjelkovic M. Dufner A. Kozma S.C. Hemmings B.A. Thomas G. Science. 1998; 279: 707-710Crossref PubMed Scopus (723) Google Scholar, 18Alessi D.R. Kozlowski M.T. Weng Q.P. Morrice N. Avruch J. Curr. Biol. 1998; 8: 69-81Abstract Full Text Full Text PDF PubMed Scopus (512) Google Scholar, 43Dennis P.B. Pullen N. Pearson R.B. Kozma S.C. Thomas G. J. Biol. Chem. 1998; 273: 14845-14852Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar, 44Weng Q.P. Kozlowski M. Belham C. Zhang A. Comb M.J. Avruch J. J. Biol. Chem. 1998; 273: 16621-16629Abstract Full Text Full Text PDF PubMed Scopus (337) Google Scholar). Using a phospho Ser411-specific antibody for p70S6K, the present study clearly demonstrated that Ang II-induced Ser411 phosphorylation of p70S6K was markedly inhibited by selective inhibitors for the signal transduction molecules that had not been implicated in GPCR-induced activation of p70S6K. Specificities of the phospho-specific antibodies (44Weng Q.P. Kozlowski M. Belham C. Zhang A. Comb M.J. Avruch J. J. Biol. Chem. 1998; 273: 16621-16629Abstract Full Text Full Text PDF PubMed Scopus (337) Google Scholar, 45Polakiewicz R.D. Schieferl S.M. Gingras A.C. Sonenberg N. Comb M.J. J. Biol. Chem. 1998; 273: 23534-23541Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar) and the inhibitors, AG1478 (40Levitzki A. Gazit A. Science. 1995; 267: 1782-1788Crossref PubMed Scopus (1613) Google Scholar), dominant-negative Ras (37Ueno H. Yamamoto H. Ito S. Li J.J. Takeshita A. Arterioscler. Thromb. Vasc. Biol. 1997; 17: 898-904Crossref PubMed Scopus (85) Google Scholar), and PD98059 (46Alessi D.R. Cuenda A. Cohen P. Dudley D.T. Saltiel A.R. J. Biol. Chem. 1995; 270: 27489-27494Abstract Full Text Full Text PDF PubMed Scopus (3246) Google Scholar) used in the present study have been well established in past publications and our previous (28Eguchi S. Matsumoto T. Motley E.D. Utsunomiya H. Inagami T. J. Biol. Chem. 1996; 271: 14169-14175Abstract Full Text Full Text PDF PubMed Scopus (263) Google Scholar, 29Eguchi S. Numaguchi K. Iwasaki H. Matsumoto T. Yamakawa T. Utsunomiya H. Motley E.D. Kawakatsu H. Owada K.M. Hirata Y. Marumo F. Inagami T. J. Biol. Chem. 1998; 273: 8890-8896Abstract Full Text Full Text PDF PubMed Scopus (503) Google Scholar) and present studies. As we demonstrated in VSMC, phosphorylation of the autoinhibitory domain of p70S6K detected by phospho-specific antibodies was a feature commonly shared by GPCRs and growth factor receptors (44Weng Q.P. Kozlowski M. Belham C. Zhang A. Comb M.J. Avruch J. J. Biol. Chem. 1998; 273: 16621-16629Abstract Full Text Full Text PDF PubMed Scopus (337) Google Scholar,45Polakiewicz R.D. Schieferl S.M. Gingras A.C. Sonenberg N. Comb M.J. J. Biol. Chem. 1998; 273: 23534-23541Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar).Several GPCR agonists have been shown to activate ERK through EGFR transactivation (47Daub H. Weiss F.U. Wallasch C. Ullrich A. Nature. 1996; 379: 557-560Crossref PubMed Scopus (1314) Google Scholar, 48Daub H. Wallasch C. Lankenau A. Herrlich A. Ullrich A. EMBO J. 1997; 16: 7032-7044Crossref PubMed Scopus (586) Google Scholar, 49Luttrell L.M. Della Rocca G.J. van Biesen T. Luttrell D.K. Lefkowitz R.J. J. Biol. Chem. 1997; 272: 4637-4644Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar), and elevation of intracellular Ca2+ is a sufficient signal for EGFR transactivation (50Rosen L.B. Greenberg M.E. Proc. Natl. Acad. Sci. U. S. A. 1996; 93: 1113-1118Crossref PubMed Scopus (172) Google Scholar). Recently, we and others have shown that Ang II and bradykinin induce Ca2+-dependent EGFR transactivation in VSMC (29Eguchi S. Numaguchi K. Iwasaki H. Matsumoto T. Yamakawa T. Utsunomiya H. Motley E.D. Kawakatsu H. Owada K.M. Hirata Y. Marumo F. Inagami T. J. Biol. 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Chem. 1998; 273: 8890-8896Abstract Full Text Full Text PDF PubMed Scopus (503) Google Scholar). Indeed, GPCR-mediated PDGFR transactivation has recently been shown to occur only when the target cell lacks EGFR (52Herrlich A. Daub H. Knebel A. Herrlich P. Ullrich A. Schultz G. Gudermann T. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 8985-8990Crossref PubMed Scopus (134) Google Scholar).Consistent with our present observation, A23187 has been shown to activate p70S6K in Swiss 3T3 fibroblasts (53Petritsch C. Woscholski R. Edelmann H.M. Parker P.J. Ballou L.M. Eur. J. Biochem. 1995; 230: 431-438Crossref PubMed Scopus (53) Google Scholar) and Graveset al. (54Graves L.M. He Y. Lambert J. Hunter D. Li X. Earp H.S. J. Biol. Chem. 1997; 272: 1920-1928Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar) have reported that Ang II-induced Ca2+-dependent p70S6K activation was completely inhibited by the tyrosine kinase inhibitor genistein in liver epithelial cells. Because AG1478 at a concentration of 250 nm blocks EGF-induced ERK phosphorylation in VSMC (29Eguchi S. Numaguchi K. Iwasaki H. Matsumoto T. Yamakawa T. Utsunomiya H. Motley E.D. Kawakatsu H. Owada K.M. Hirata Y. Marumo F. Inagami T. J. Biol. Chem. 1998; 273: 8890-8896Abstract Full Text Full Text PDF PubMed Scopus (503) Google Scholar) and because it did not completely inhibit Ang II-induced p70S6Kactivation, other Ca2+-dependent tyrosine kinase(s) may also contribute to the activation of p70S6K. Likely candidate(s) mediating the AG1478-insensitive p70S6Kactivation could be a novel Ca2+-dependent tyrosine kinase, Pyk2, and/or c-Src, both of which have also been implicated in GPCR-mediated ERK activation in many cells (55Lev S. Moreno H. Martinez R. Canoll P. Peles E. Musacchio J.M. Plowman G.D. Rudy B. Schlessinger J. Nature. 1995; 376: 737-745Crossref PubMed Scopus (1246) Google Scholar, 56Luttrell L.M. Hawes B.E. van Biesen T. Luttrell D.K. Lansing T.J. Lefkowitz R.J. J. Biol. 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Govindarajan G. Griffin T.M. Byron K.L. Samarel A.M. Lucchesi P.A. Circ. Res. 1998; 83: 841-851Crossref PubMed Scopus (135) Google Scholar, 61Eguchi S. Iwasaki H. Inagami T. Numaguchi K. Yamakawa T. Motley E.D. Owada K.M. Marumo F. Hirata Y. Hypertension. 1999; 33: 201-206Crossref PubMed Google Scholar) and Pyk2 associates with c-Src (60Sabri A. Govindarajan G. Griffin T.M. Byron K.L. Samarel A.M. Lucchesi P.A. Circ. Res. 1998; 83: 841-851Crossref PubMed Scopus (135) Google Scholar, 61Eguchi S. Iwasaki H. Inagami T. Numaguchi K. Yamakawa T. Motley E.D. Owada K.M. Marumo F. Hirata Y. Hypertension. 1999; 33: 201-206Crossref PubMed Google Scholar). We have further showed that these events were not inhibited by AG1478 (61Eguchi S. Iwasaki H. Inagami T. Numaguchi K. Yamakawa T. Motley E.D. Owada K.M. Marumo F. Hirata Y. Hypertension. 1999; 33: 201-206Crossref PubMed Google Scholar). c-Src appeared to function upstream of GPCR-induced EGFR transactivation (29Eguchi S. Numaguchi K. Iwasaki H. Matsumoto T. Yamakawa T. Utsunomiya H. Motley E.D. Kawakatsu H. Owada K.M. Hirata Y. Marumo F. Inagami T. J. Biol. Chem. 1998; 273: 8890-8896Abstract Full Text Full Text PDF PubMed Scopus (503) Google Scholar, 49Luttrell L.M. Della Rocca G.J. van Biesen T. Luttrell D.K. Lefkowitz R.J. J. Biol. Chem. 1997; 272: 4637-4644Abstract Full Text Full Text PDF PubMed Scopus (426) Google Scholar), and we found that the inducible association of c-Src with EGFR by Ang II was insensitive to AG1478 in VSMC (29Eguchi S. Numaguchi K. Iwasaki H. Matsumoto T. Yamakawa T. Utsunomiya H. Motley E.D. Kawakatsu H. Owada K.M. Hirata Y. Marumo F. Inagami T. J. Biol. Chem. 1998; 273: 8890-8896Abstract Full Text Full Text PDF PubMed Scopus (503) Google Scholar). However, whether signals from these tyrosine kinases are sufficient to the activation of p70S6K remains to be determined.Several lines of evidence have indicated that ERK and p70S6K lie on separate signaling pathways (6Chung J. Grammer T.C. Lemon K.P. Kazlauskas A. Blenis J. Nature. 1994; 370: 71-75Crossref PubMed Scopus (656) Google Scholar, 10Ballou L.M. Luther H. Thomas G. Nature. 1991; 349: 348-350Crossref PubMed Scopus (152) Google Scholar, 11Ming X.F. Burgering B.M. Wennstrom S. Claesson W.L. Heldin C.H. Bos J.L. Kozma S.C. Thomas G. Nature. 1994; 371: 426-429Crossref PubMed Scopus (204) Google Scholar, 12Sakaue M. Bowtell D. Kasuga M. Mol. Cell. Biol. 1995; 15: 379-388Crossref PubMed Scopus (60) Google Scholar). Indeed, we observed that insulin induced Ser411phosphorylation of p70S6K without affecting Tyr204 phosphorylation of ERK in VSMC and the insulin-induced Ser411 phosphorylation was not inhibited by the MEK inhibitor PD98059. In CHO cells, PD98059 had no effect on Thr421/Ser424 phosphorylation of p70S6K in response to a Gi-coupled μ-opioid receptor stimulation (45Polakiewicz R.D. Schieferl S.M. Gingras A.C. Sonenberg N. Comb M.J. J. Biol. 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• W2009650205 title "Intracellular Signaling of Angiotensin II-induced p70 S6 Kinase Phosphorylation at Ser411 in Vascular Smooth Muscle Cells" @default.
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