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• W2019964639 abstract "Insulin receptor substrates (IRSs) are tyrosine-phosphorylated following stimulation with insulin, insulin-like growth factors (IGFs), and interleukins. A key question is whether different IRSs play different roles to mediate insulin's metabolic and growth-promoting effects. In a novel system of insulin receptor-deficient hepatocytes, insulin fails to (i) stimulate glucose phosphorylation, (ii) enhance glycogen synthesis, (iii) suppress glucose production, and (iv) promote mitogenesis. However, insulin's ability to induce IRS-1 and gab-1 phosphorylation and binding to phosphatidylinositol (PI) 3-kinase is unaffected, by virtue of the compensatory actions of IGF-1 receptors. In contrast, phosphorylation of IRS-2 and generation of IRS-2/PI 3-kinase complexes are markedly reduced. Thus, absence of insulin receptors selectively reduces IRS-2, but not IRS-1 phosphorylation, and the impairment of IRS-2 activation is associated with lack of insulin effects. To address whether phosphorylation of additional IRSs is also affected, we analyzed phosphotyrosine-containing proteins in PI 3-kinase immunoprecipitates from insulin-treated cells. However, these experiments indicate that IRS-1 and IRS-2 are the main PI 3-kinase-bound proteins in hepatocytes. These data identify IRS-2 as the main effector of both the metabolic and growth-promoting actions of insulin through PI 3-kinase in hepatocytes, and IRS-1 as the main substrate mediating the mitogenic actions of IGF-1 receptors. Insulin receptor substrates (IRSs) are tyrosine-phosphorylated following stimulation with insulin, insulin-like growth factors (IGFs), and interleukins. A key question is whether different IRSs play different roles to mediate insulin's metabolic and growth-promoting effects. In a novel system of insulin receptor-deficient hepatocytes, insulin fails to (i) stimulate glucose phosphorylation, (ii) enhance glycogen synthesis, (iii) suppress glucose production, and (iv) promote mitogenesis. However, insulin's ability to induce IRS-1 and gab-1 phosphorylation and binding to phosphatidylinositol (PI) 3-kinase is unaffected, by virtue of the compensatory actions of IGF-1 receptors. In contrast, phosphorylation of IRS-2 and generation of IRS-2/PI 3-kinase complexes are markedly reduced. Thus, absence of insulin receptors selectively reduces IRS-2, but not IRS-1 phosphorylation, and the impairment of IRS-2 activation is associated with lack of insulin effects. To address whether phosphorylation of additional IRSs is also affected, we analyzed phosphotyrosine-containing proteins in PI 3-kinase immunoprecipitates from insulin-treated cells. However, these experiments indicate that IRS-1 and IRS-2 are the main PI 3-kinase-bound proteins in hepatocytes. These data identify IRS-2 as the main effector of both the metabolic and growth-promoting actions of insulin through PI 3-kinase in hepatocytes, and IRS-1 as the main substrate mediating the mitogenic actions of IGF-1 receptors. Insulin, IGF-1, 1The abbreviations used are: IGF, insulin-like growth factor; IRS, insulin receptor substrate; WT, wild type; PI, phosphatidylinositol. 1The abbreviations used are: IGF, insulin-like growth factor; IRS, insulin receptor substrate; WT, wild type; PI, phosphatidylinositol. and IGF-2, acting through insulin and IGF-1 receptors, promote a wide range of metabolic and growth-promoting functions in typical insulin target cells, such as liver, muscle, and fat, and to a lesser extent in other tissues. The mechanism by which insulin regulates energy metabolism and promotes cell growth has been extensively studied. In recent years, a consensus has emerged that phosphorylation of IRS molecules by the insulin receptor kinase is important for insulin action (1White M.F. Kahn C.R. J. Biol. Chem. 1994; 269: 1-4Abstract Full Text PDF PubMed Google Scholar). IRS molecules engage in the formation of signaling complexes with numerous adapter molecules and enzymes via their pY-X-X-M motifs (2Sun X.J. Rothenberg P. Kahn C.R. Backer J.M. Araki E. Wilden P.A. Cahill D.A. Goldstein B.J. White M.F. Nature. 1991; 352: 73-77Crossref PubMed Scopus (1275) Google Scholar, 3Sun X.J. Wang L.M. Zhang Y. Yenush L. Myers M.J. Glasheen E. Lane W.S. Pierce J.H. White M.F. Nature. 1995; 377: 173-177Crossref PubMed Scopus (763) Google Scholar, 4Lavan B.E. Lane W.S. Lienhard G.E. J. Biol. Chem. 1997; 272: 11439-11443Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar, 5Lavan B.E. Fantin V.R. Chang E.T. Lane W.S. Keller S.R. Lienhard G.E. J. Biol. Chem. 1997; 272: 21403-21407Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar, 6Holgado-Madruga M. Emlet D.R. Moscatello D.K. Godwin A.K. Wong A.J. Nature. 1996; 379: 560-564Crossref PubMed Scopus (599) Google Scholar). Thus, the IRS signaling system provides an elegant explanation for the diversity of insulin signaling (7Yenush L. White M.F. Bioessays. 1997; 19: 491-500Crossref PubMed Scopus (252) Google Scholar). Nevertheless, the role of different IRSs in insulin signaling, as well as the role of the numerous additional substrates of the insulin receptor kinase that are distinct from IRS has remained elusive.Progress in this area has been hampered by the lack of suitablein vitro systems in which phosphorylation of individual molecules can be correlated with specific biologic functions. In fact, insulin-responsive cell lines such as 3T3-L1 adipocytes or L6 myoblasts possess an endogenous complement of signaling molecules, so that the effects of individual components can be addressed only by way of overexpression or inhibition experiments. It is significant that much progress in our understanding of the IRS system has derived from studies of the myeloid cell line 32D, which carries a functional knock-out of these molecules (8Wang L.-M. Myers M.G. Sun X.-J. Aaronson S.A. White M.F. Pierce J.H. Science. 1993; 261: 1591-1594Crossref PubMed Scopus (365) Google Scholar, 9Wang L.M. Keegan A.D. Li W. Lienhard G.E. Pacini S. Gutkind J.S. Myers M.J. Sun X.J. White M.F. Aaronson S.A. Pierce J.H. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 4032-4036Crossref PubMed Scopus (166) Google Scholar, 10Myers Jr., M.J. Grammer T.C. Wang L.M. Sun X.J. Pierce J.H. Blenis J. White M.F. J. Biol. Chem. 1994; 269: 28783-28789Abstract Full Text PDF PubMed Google Scholar). However, 32D cells may not be representative of classic target tissues of insulin action.Targeted mutagenesis of genes of the insulin and IGF signaling system in mice has provided clues as to the functional differences among related molecules (11Accili D. Trends Endocrinol. Metab. 1997; 8: 101-104Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, 12Efstratiadis A. Exp. Clin. Endocrinol. Diabetes. 1996; 104: 4-6Crossref PubMed Scopus (9) Google Scholar). We and others, for example, have shown that insulin receptors are indeed the master switch of the insulin signaling pathway (13Accili D. Drago J. Lee E.J. Johnson M.D. Cool M.H. Salvatore P. Asico L.D. Jose P.A. Taylor S.I. Westphal H. Nat. Genet. 1996; 12: 106-109Crossref PubMed Scopus (474) Google Scholar, 14Joshi R.L. Lamothe B. Cordonnier N. Mesbah K. Monthioux E. Jami J. Bucchini D. EMBO J. 1996; 15: 1542-1547Crossref PubMed Scopus (242) Google Scholar), and that IGF-1 receptors contribute little to metabolic regulation (15Liu J.P. Baker J. Perkins A.S. Robertson E.J. Efstratiadis A. Cell. 1993; 75: 59-72Abstract Full Text PDF PubMed Scopus (2553) Google Scholar, 16Baker J. Liu J.P. Robertson E.J. Efstratiadis A. Cell. 1993; 75: 73-82Abstract Full Text PDF PubMed Scopus (2036) Google Scholar, 17Di Cola G. Cool M.H. Accili D. J. Clin. Invest. 1997; 99: 2538-2544Crossref PubMed Scopus (126) Google Scholar). Likewise, the phenotype of mice with a genetic ablation of IRS-1 has suggested that IRS-1 plays a more important role in mediating growth than metabolic responses (18Araki E. Lipes M.A. Patti M.E. Bruning J.C. Haag B.r. Johnson R.S. Kahn C.R. Nature. 1994; 372: 186-190Crossref PubMed Scopus (1086) Google Scholar, 19Tamemoto H. Kadowaki T. Tobe K. Yagi T. Sakura H. Hayakawa T. Terauchi Y. Ueki K. Kaburagi Y. Satoh S. Sekihara H. Yoshioka S. Horikoshi H. Furuta Y. Ikawa Y. Kasuga M. Yazaki Y. Aizawa S. Nature. 1994; 372: 182-186Crossref PubMed Scopus (898) Google Scholar). Interestingly, however, combined heterozygosity for an insulin receptor and an IRS-1 null allele triggers synergistic interactions to impair insulin action and causes insulin-resistant diabetes in mice, suggesting that IRS-1 can also affect metabolism (20Bruning J.C. Winnay J. Bonner W.S. Taylor S.I. Accili D. Kahn C.R. Cell. 1997; 88: 561-572Abstract Full Text Full Text PDF PubMed Scopus (462) Google Scholar). On the other hand, mice lacking IRS-2 develop lethal diabetic ketoacidosis as a result of combined insulin resistance and insulin deficiency, indicating that IRS-2 plays a crucial role in the development of mechanisms regulating fuel homeostasis (21Withers D.J. Sanchez-Gutierrez J. Towery H. Burks D.J. Ren J.-M. Previs S. Zhang Y. Bernal D. Pons S. Shulman G.I. Bonner-Weir S. White M.F. Nature. 1998; 391: 900-904Crossref PubMed Scopus (1325) Google Scholar).The derivation of cell lines from mice with targeted mutations provides an important tool to dissect the function of these molecules in vitro. For example, Bruning et al. (22Bruning J.C. Winnay J. Cheatham B. Kahn C.R. Mol. Cell. Biol. 1997; 17: 1513-1521Crossref PubMed Scopus (190) Google Scholar) have been able to show that IRS-1 and IRS-2 are not functionally interchangeable in mediating various growth-promoting functions of IGF-1 in fibroblasts of IRS-1-deficient mice.In this study, we have analyzed insulin action in permanent cultures of hepatocytes from mice lacking insulin receptors. We generated these cells using a well established procedure entailing transformation with a temperature-sensitive mutant SV40 virus (23Chou J.Y. Methods Emzymol. 1985; 109: 385-396Crossref PubMed Scopus (36) Google Scholar). We asked whether, in the absence of insulin receptors, IGF-1 receptors could mediate the typical metabolic and growth-promoting responses of insulin in hepatocytes. We report that insulin, acting through the IGF-1 receptor, mediates IRS-1, but not IRS-2 phosphorylation, and that the failure to phosphorylate IRS-2 correlates with the inability of these cells to mediate insulin's characteristic actions. Phosphorylation of gab-1, and association of other phosphotyrosine-containing proteins with the p85 subunit of PI 3-kinase, were similar in normal and insulin receptor-deficient cells. These findings correlate IRS-2 phosphorylation with both the metabolic and growth-promoting actions of insulin, and suggest that individual IRS molecules play a more specific role in signal transduction than previously recognized.DISCUSSIONIn these investigations, we have analyzed the correlation between IRSs phosphorylation and insulin action in hepatocytes derived from insulin receptor-deficient mice. We provide evidence that impaired activation of IRS-2 in these cells is associated with failure of both metabolic and growth-promoting actions of insulin. An important result of the present study is that ablation of insulin receptors results in a selective loss of IRS-2 phosphorylation, in the absence of detectable changes in IRS-1 phosphorylation. Indirect evidence suggests that additional IRSs are minor components of the IRS signaling system in this cell type. Thus, these data support the notion that signaling from insulin receptors to IRS-2 is required for the characteristic actions of insulin in liver. Since our data were obtained in the context of a physiologic target cell of insulin action, we believe that they add significant new information to our understanding of the insulin signaling system.The link between impaired phosphorylation of IRS-2 and impaired insulin action is further demonstrated by the decrease in the formation of IRS-2/PI 3-kinase complexes in −/− cells. There is substantial evidence that PI 3-kinase is required for many, if not all, of insulin actions (35Berger J. Hayes N. Szalkowski D.M. Zhang B. Biochem. Biophys. Res. Commun. 1994; 205: 570-576Crossref PubMed Scopus (36) Google Scholar, 36Rahn T. Ridderstrale M. Tornqvist H. Manganiello V. Fredrikson G. Belfrage P. Degerman E. FEBS Lett. 1994; 350: 314-318Crossref PubMed Scopus (119) Google Scholar, 37Shimizu Y. Shimazu T. Biochem. Biophys. Res. Commun. 1994; 202: 660-665Crossref PubMed Scopus (42) Google Scholar, 38Kotani K. Yonezawa K. Hara K. Ueda H. Kitamura Y. Sakaue H. Ando A. Chavanieu A. Calas B. Grigorescu F. Waterfield M.D. Kasuga M. EMBO J. 1994; 13: 2313-2321Crossref PubMed Scopus (326) Google Scholar, 39Okada T. Kawano Y. Sakakibara T. Hazeki O. Ui M. J. Biol. Chem. 1994; 269: 3568-3573Abstract Full Text PDF PubMed Google Scholar, 40Su T.-Z. Wang M. Syu L.-J. Saltiel A.R. Oxender D.L. J. Biol. 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Chem. 1995; 270: 15501-15506Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar). While in this study we did not measure PI 3-kinase activity directly, it is well established that insulin activates PI 3-kinase by causing IRSs to bind to the SH2 domains of the p85 subunit (29Nikolic-Rordorf T. Van Horn D. Chen D. White M.F. Backer J.M. J. Biol. Chem. 1995; 270: 3662-3666Abstract Full Text Full Text PDF PubMed Scopus (213) Google Scholar, 30Sun X.J. Crimmins D.L. Myers M.J. Miralpeix M. White M.F. Mol. Cell. Biol. 1993; 13: 7418-7428Crossref PubMed Google Scholar, 31Myers M.J. Backer J.M. Sun X.J. Shoelson S. Hu P. Schlessinger J. Yoakim M. Schaffhausen B. White M.F. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 10350-10354Crossref PubMed Scopus (382) Google Scholar). Thus, there is an excellent correlation between co-precipitation of IRSs with p85 and PI 3-kinase activity. Our analysis of the patterns of tyrosine-phosphorylated proteins detected in p85 immunoprecipitates indicates that the main proteins bound to p85 in hepatocytes are indeed IRS-1 and IRS-2, and therefore account for most of PI 3-kinase activity elicited by insulin in these cells. Furthermore, we have recently been able to show that insulin fails to stimulate Akt activity in −/− cells, which is consistent with an impairment of PI 3-kinase activity 2B.-C. Park and D. Accili, unpublished observation. (47Burgering B.M. Coffer P.J. Nature. 1995; 376: 599-602Crossref PubMed Scopus (1871) Google Scholar, 48Cross D.A. Alessi D.R. Cohen P. Andjelkovich M. Hemmings B.A. Nature. 1995; 378: 785-789Crossref PubMed Scopus (4324) Google Scholar, 49Alessi D.R. Andjelkovic M. Caudwell B. Cron P. Morrice N. Cohen P. Hemmings B.A. EMBO J. 1996; 15: 6541-6551Crossref PubMed Scopus (2495) Google Scholar, 50Kohn A.D. Kovacina K.S. Roth R.A. EMBO J. 1995; 14: 4288-4295Crossref PubMed Scopus (318) Google Scholar). These data provide support to the notion that impairment of IRS-2 phosphorylation in −/− cells is one of the mechanisms of the failure of insulin action, and not an epiphenomenon.The conclusion that IRS-2 plays an important role in mediating the metabolic actions of insulin is supported by several lines of independent evidence. IRS-2-deficient mice are diabetic as a result of combined insulin resistance and impaired insulin production (21Withers D.J. Sanchez-Gutierrez J. Towery H. Burks D.J. Ren J.-M. Previs S. Zhang Y. Bernal D. Pons S. Shulman G.I. Bonner-Weir S. White M.F. Nature. 1998; 391: 900-904Crossref PubMed Scopus (1325) Google Scholar), while IRS-1-deficient mice are growth retarded, but mildly insulin-resistant (18Araki E. Lipes M.A. Patti M.E. Bruning J.C. Haag B.r. Johnson R.S. Kahn C.R. Nature. 1994; 372: 186-190Crossref PubMed Scopus (1086) Google Scholar, 19Tamemoto H. Kadowaki T. Tobe K. Yagi T. Sakura H. Hayakawa T. Terauchi Y. Ueki K. Kaburagi Y. Satoh S. Sekihara H. Yoshioka S. Horikoshi H. Furuta Y. Ikawa Y. Kasuga M. Yazaki Y. Aizawa S. Nature. 1994; 372: 182-186Crossref PubMed Scopus (898) Google Scholar). Furthermore, normal insulin action in liver of IRS-1-deficient mice is associated with increased phosphorylation of IRS-2 (51Yamauchi Y. Tobe K. Tamemoto H. Kohjiro U. Kaburagi Y. Yamamoto-Honda R. Takahashi Y. Yoshizawa F. Aizawa S. Akanuma Y. Sonenberg N. Yazaki Y. Kadowaki T. Mol. Cell. Biol. 1996; 16: 3074-3084Crossref PubMed Scopus (248) Google Scholar). Based on the phenotypes of insulin receptor-, IGF-1 receptor-, IRS-1-, and IRS-2-deficient mice (13Accili D. Drago J. Lee E.J. Johnson M.D. Cool M.H. Salvatore P. Asico L.D. Jose P.A. Taylor S.I. Westphal H. Nat. Genet. 1996; 12: 106-109Crossref PubMed Scopus (474) Google Scholar, 14Joshi R.L. Lamothe B. Cordonnier N. Mesbah K. Monthioux E. Jami J. Bucchini D. EMBO J. 1996; 15: 1542-1547Crossref PubMed Scopus (242) Google Scholar, 15Liu J.P. Baker J. Perkins A.S. Robertson E.J. Efstratiadis A. Cell. 1993; 75: 59-72Abstract Full Text PDF PubMed Scopus (2553) Google Scholar, 18Araki E. Lipes M.A. Patti M.E. Bruning J.C. Haag B.r. Johnson R.S. Kahn C.R. Nature. 1994; 372: 186-190Crossref PubMed Scopus (1086) Google Scholar, 19Tamemoto H. Kadowaki T. Tobe K. Yagi T. Sakura H. Hayakawa T. Terauchi Y. Ueki K. Kaburagi Y. Satoh S. Sekihara H. Yoshioka S. Horikoshi H. Furuta Y. Ikawa Y. Kasuga M. Yazaki Y. Aizawa S. Nature. 1994; 372: 182-186Crossref PubMed Scopus (898) Google Scholar, 21Withers D.J. Sanchez-Gutierrez J. Towery H. Burks D.J. Ren J.-M. Previs S. Zhang Y. Bernal D. Pons S. Shulman G.I. Bonner-Weir S. White M.F. Nature. 1998; 391: 900-904Crossref PubMed Scopus (1325) Google Scholar), one has to conclude that IRS-1 is predominantly an IGF-1 receptor substrate, and IRS-2 an insulin receptor substrate. This conclusion is strengthened by the present findings, indicating that insulin receptors are required for optimal IRS-2 phosphorylation. By suggesting that IRS-2 functions primarily as an insulin receptor substrate, our data provide a compelling explanation for the phenotype of mice lacking IRS-2 (21Withers D.J. Sanchez-Gutierrez J. Towery H. Burks D.J. Ren J.-M. Previs S. Zhang Y. Bernal D. Pons S. Shulman G.I. Bonner-Weir S. White M.F. Nature. 1998; 391: 900-904Crossref PubMed Scopus (1325) Google Scholar), and corroborate the findings of Bruning et al.that IRS-1 and IRS-2 are functionally distinct molecules (22Bruning J.C. Winnay J. Cheatham B. Kahn C.R. Mol. Cell. Biol. 1997; 17: 1513-1521Crossref PubMed Scopus (190) Google Scholar). Substrate selection, however, is likely to be a more complex eventin vivo, as indicated by studies of mice with combined null mutations of the insulin receptor and IRS-1 genes, which develop insulin resistant diabetes with significantly higher frequency than mice heterozygous for each individual mutation (20Bruning J.C. Winnay J. Bonner W.S. Taylor S.I. Accili D. Kahn C.R. Cell. 1997; 88: 561-572Abstract Full Text Full Text PDF PubMed Scopus (462) Google Scholar).An important question raised from our studies is why IGF-1 receptors fail to phosphorylate IRS-2 as insulin receptors do. There is ample evidence that IRS-1 and IRS-2 utilize different mechanisms to interact with their receptor partners (52He W. Craparo A. Zhu Y. O'Neill T.J. Wang L.-M. Pierce J.H. Gustafson T.A. J. Biol. Chem. 1996; 271: 11641-11645Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar, 53Sawka-Verhelle D. Baron V. Mothe I. Filloux C. White M.F. Van Obberghen E. J. Biol. Chem. 1997; 272: 16414-16420Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar, 54Sawka-Verhelle D. Tartare-Deckert S. White M.F. Van Obberghen E. J. Biol. Chem. 1996; 271: 5980-5983Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar). This evidence, however, does not support a different mode of interaction of insulin and IGF-1 receptors with IRS-1 and IRS-2. An alternative possibility is that the subcellular localization of IRS-2 in hepatocytes prevents its efficient phosphorylation by IGF-1 receptors. A similar mechanism has been postulated to explain the differences between epidermal growth factor and insulin signaling (55Di Guglielmo G.M. Baass P.B. Ou W.-J. Posner B.I. Bergeron J.J.M. EMBO J. 1994; 13: 4269-4277Crossref PubMed Scopus (299) Google Scholar), but there is no direct evidence that a similar mechanism may be at play in this instance.The failure of insulin at high doses to activate metabolic responses through IGF-1 receptors is an important finding and deserves further comment. There has been considerable controversy over the ability of IGF-1 receptors to mediate metabolic actions (56Moses A.C. Morrow L.A. O'Brien M. Moller D.E. Flier J.S. Diabetes Res. Clin. Pract. 1995; 28: S185-S194Abstract Full Text PDF PubMed Scopus (39) Google Scholar). We have previously shown that IGF-1 receptors are weak mediators of metabolic effects in mice lacking insulin receptors (17Di Cola G. Cool M.H. Accili D. J. Clin. Invest. 1997; 99: 2538-2544Crossref PubMed Scopus (126) Google Scholar). We postulated that IGF-1 may enhance peripheral glucose uptake in muscle and decrease hepatic gluconeogenesis. Based on those data, we proposed that IGF-1 may act on hepatic glucose production either directly through IGF-1 receptors, or indirectly through inhibition of glucagon secretion. The failure of IGF-1 receptors to impinge on hepatic glucose metabolism favors an indirect mechanism as a more likely explanation of our previous findings, but further studies comparing gluconeogenetic rates are required.The impairment of insulin-mediated growth in −/− cells correlated with the loss of insulin receptor-mediated IRS-2 phosphorylation, suggesting that growth-promoting signaling of insulin receptors occurs prevalently through IRS-2. On the other hand, IGF-1-dependent growth occurred normally in −/− cells, indicating that IGF-1 receptors signal through IRS-1, phosphorylation of which is not affected in −/− cells. It is possible that some of the effects of insulin or IGF-1 on growth are mediated by shc through the grb-2/mSOS pathway to mitogen-activated protein kinase (41Shepherd P.R. Nave B.T. Rincon J. Haigh R.J. Foulstone E. Proud C. Zierath J.R. Siddle K. Wallberg-Henriksson H. Diabetologia. 1997; 40: 1172-1177Crossref PubMed Scopus (56) Google Scholar, 57Sasaoka T. Rose D.W. Jhun B.H. Saltiel A.R. Draznin B. Olefsky J.M. J. Biol. Chem. 1994; 269: 13689-13694Abstract Full Text PDF PubMed Google Scholar,58Ouwens D.M. van der Zon G.C. Pronk G.J. Bos J.L. Moller W. Cheatham B. Kahn C.R. Maassen J.A. J. Biol. Chem. 1994; 269: 33116-33122Abstract Full Text PDF PubMed Google Scholar), although this point remains controversial (59Yamauchi K. Pessin J.E. J. Biol. Chem. 1994; 269: 31107-31114Abstract Full Text PDF PubMed Google Scholar, 60Chung J. Grammer T.C. Lemon K.P. Kazlauskas A. Blenis J. Nature. 1994; 370: 71-75Crossref PubMed Scopus (656) Google Scholar, 61Yonezawa K. Ando A. Kaburagi Y. Yamamoto-Honda R. Kitamura T. Hara K. Nakafuku M. Okabayashi Y. Kadowaki T. Kaziro Y. J. Biol. Chem. 1994; 269: 4634-4640Abstract Full Text PDF PubMed Google Scholar). This possibility is currently under investigation. However, it is interesting to note that Bruning and co-workers have shown that IGF-1-dependent growth of IRS-1-deficient fibroblasts is impaired despite normal activation of mitogen-activated protein kinase, and cannot be rescued by IRS-2, consistent with our model in which IGF-1 receptors utilize primarily IRS-1 to mediate their actions on cell growth (22Bruning J.C. Winnay J. Cheatham B. Kahn C.R. Mol. Cell. Biol. 1997; 17: 1513-1521Crossref PubMed Scopus (190) Google Scholar). The impairment of IGF-2-mediated growth in −/− cells is consistent with previous evidence from our laboratory and others that insulin receptors mediate the growth-promoting actions of IGF-2 (62Morrione A. Valentinis B. Xu S.Q. Yumet G. Louvi A. Efstratiadis A. Baserga R. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 3777-3782Crossref PubMed Scopus (193) Google Scholar, 63Louvi A. Accili D. Efstratiadis A. Dev. Biol. 1997; 189: 33-48Crossref PubMed Scopus (319) Google Scholar).In conclusion, our data support a model in which the specificity of insulin signaling in liver is bestowed by the formation of a signaling complex between insulin receptors and IRS-2. It remains to be seen whether a similar mechanism operates in other cell types, for example in insulin-dependent translocation of glucose transporters in skeletal muscle and adipose tissue. Insulin, IGF-1, 1The abbreviations used are: IGF, insulin-like growth factor; IRS, insulin receptor substrate; WT, wild type; PI, phosphatidylinositol. 1The abbreviations used are: IGF, insulin-like growth factor; IRS, insulin receptor substrate; WT, wild type; PI, phosphatidylinositol. and IGF-2, acting through insulin and IGF-1 receptors, promote a wide range of metabolic and growth-promoting functions in typical insulin target cells, such as liver, muscle, and fat, and to a lesser extent in other tissues. The mechanism by which insulin regulates energy metabolism and promotes cell growth has been extensively studied. In recent years, a consensus has emerged that phosphorylation of IRS molecules by the insulin receptor kinase is important for insulin action (1White M.F. Kahn C.R. J. Biol. Chem. 1994; 269: 1-4Abstract Full Text PDF PubMed Google Scholar). IRS molecules engage in the formation of signaling complexes with numerous adapter molecules and enzymes via their pY-X-X-M motifs (2Sun X.J. Rothenberg P. Kahn C.R. Backer J.M. Araki E. Wilden P.A. Cahill D.A. Goldstein B.J. White M.F. Nature. 1991; 352: 73-77Crossref PubMed Scopus (1275) Google Scholar, 3Sun X.J. Wang L.M. Zhang Y. Yenush L. Myers M.J. Glasheen E. Lane W.S. Pierce J.H. White M.F. Nature. 1995; 377: 173-177Crossref PubMed Scopus (763) Google Scholar, 4Lavan B.E. Lane W.S. Lienhard G.E. J. Biol. Chem. 1997; 272: 11439-11443Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar, 5Lavan B.E. Fantin V.R. Chang E.T. Lane W.S. Keller S.R. Lienhard G.E. J. Biol. Chem. 1997; 272: 21403-21407Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar, 6Holgado-Madruga M. Emlet D.R. Moscatello D.K. Godwin A.K. Wong A.J. Nature. 1996; 379: 560-564Crossref PubMed Scopus (599) Google Scholar). Thus, the IRS signaling system provides an elegant explanation for the diversity of insulin signaling (7Yenush L. White M.F. Bioessays. 1997; 19: 491-500Crossref PubMed Scopus (252) Google Scholar). Nevertheless, the role of different IRSs in insulin signaling, as well as the role of the numerous additional substrates of the insulin receptor kinase that are distinct from IRS has remained elusive. Progress in this area has been hampered by the lack of suitablein vitro systems in which phosphorylation of individual molecules can be correlated with specific biologic functions. In fact, insulin-responsive cell lines such as 3T3-L1 adipocytes or L6 myoblasts possess an endogenous complement of signaling molecules, so that the effects of individual components can be addressed only by way of overexpression or inhibition experiments. It is significant that much progress in our understanding of the IRS system has derived from studies of the myeloid cell line 32D, which carries a functional knock-out of these molecules (8Wang L.-M. Myers M.G. Sun X.-J. Aaronson S.A. White M.F. Pierce J.H. Science. 1993; 261: 1591-1594Crossref PubMed Scopus (365) Google Scholar, 9Wang L.M. Keegan A.D. Li W. Lienhard G.E. Pacini S. Gutkind J.S. Myers M.J. Sun X.J. White M.F. Aaronson S.A. Pierce J.H. Proc. Natl. Acad. Sci. U. S. A. 1993; 90: 4032-4036Crossref PubMed Scopus (166) Google Scholar, 10Myers Jr., M.J. Grammer T.C. Wang L.M. Sun X.J. Pierce J.H. Blenis J. White M.F. J. Biol. Chem. 1994; 269: 28783-28789Abstract Full Text PDF PubMed Google Scholar). 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