Epidermal Growth Factor and Transforming Growth Factor α Mimic the Effects of Insulin in Human Fat Cells and Augment Downstream Signaling in Insulin Resistance

The ability of the growth factors epidermal growth factor (EGF), transforming growth factor α, and platelet-derived growth factor to exert insulin-like effects on glucose transport and lipolysis were examined in human and rat fat cells. No effects were found in rat fat cells, whereas EGF (EC50 for glucose transport ∼0.02 nm) and transforming growth factor α (EC50 ∼0.2 nm), but not platelet-derived growth factor, mimicked the effects of insulin (EC50 ∼0.2 nm) on both pathways. EGF receptors, but not EGF, were abundantly expressed in human fat cells as well as in human skeletal muscle. EGF increased the tyrosine phosphorylation of several proteins (the EGF receptor, insulin receptor substrate (IRS)-1, IRS-2, and Grb2-associated binder 1), whereas Shc and Gab2 were only weakly and inconsistently phosphorylated. p85, the regulatory subunit of phosphatidylinositol 3-kinase (PI 3-kinase), was also found to associate with all of these docking molecules, showing that EGF activated PI 3-kinase pools that were additional to those of insulin. EGF and/or insulin increased protein kinase B/Akt serine phosphorylation to a similar extent, whereas mitogen-activated protein kinase phosphorylation was more pronounced for EGF than for insulin. The impaired insulin-stimulated downstream signaling, measured as protein kinase B/Akt serine phosphorylation, in insulin-resistant cells (Type 2 diabetes) was improved by the addition of EGF. Thus, EGF receptors, but not EGF, are abundantly expressed in human fat cells and skeletal muscle. EGF mimics the effects of insulin on both the metabolic and mitogenic pathways but utilize in part different signaling pathways. Both insulin and EGF increase the tyrosine phosphorylation and activation of IRS-1 and IRS-2, whereas EGF is also capable of activating additional PI 3-kinase pools and, thus, can augment the downstream signaling of insulin in insulin-resistant states like Type 2 diabetes. The ability of the growth factors epidermal growth factor (EGF), transforming growth factor α, and platelet-derived growth factor to exert insulin-like effects on glucose transport and lipolysis were examined in human and rat fat cells. No effects were found in rat fat cells, whereas EGF (EC50 for glucose transport ∼0.02 nm) and transforming growth factor α (EC50 ∼0.2 nm), but not platelet-derived growth factor, mimicked the effects of insulin (EC50 ∼0.2 nm) on both pathways. EGF receptors, but not EGF, were abundantly expressed in human fat cells as well as in human skeletal muscle. EGF increased the tyrosine phosphorylation of several proteins (the EGF receptor, insulin receptor substrate (IRS)-1, IRS-2, and Grb2-associated binder 1), whereas Shc and Gab2 were only weakly and inconsistently phosphorylated. p85, the regulatory subunit of phosphatidylinositol 3-kinase (PI 3-kinase), was also found to associate with all of these docking molecules, showing that EGF activated PI 3-kinase pools that were additional to those of insulin. EGF and/or insulin increased protein kinase B/Akt serine phosphorylation to a similar extent, whereas mitogen-activated protein kinase phosphorylation was more pronounced for EGF than for insulin. The impaired insulin-stimulated downstream signaling, measured as protein kinase B/Akt serine phosphorylation, in insulin-resistant cells (Type 2 diabetes) was improved by the addition of EGF. Thus, EGF receptors, but not EGF, are abundantly expressed in human fat cells and skeletal muscle. EGF mimics the effects of insulin on both the metabolic and mitogenic pathways but utilize in part different signaling pathways. Both insulin and EGF increase the tyrosine phosphorylation and activation of IRS-1 and IRS-2, whereas EGF is also capable of activating additional PI 3-kinase pools and, thus, can augment the downstream signaling of insulin in insulin-resistant states like Type 2 diabetes. epidermal growth factor mitogen-activated protein platelet-derived growth factor Src homology 2 and 3, respectively phosphatidylinositol insulin receptor substrate epidermal growth factor receptor(s) protein kinase B 6-carboxyfluorescein 6-carboxytetramethylrhodamine reverse transcriptase The insulin receptor belongs to a large family of receptor tyrosine kinases, also including receptors for epidermal growth factor (EGF),1 platelet-derived growth factor (PDGF), hepatocyte growth factor, and fibroblast growth factor (1Schlessinger J. Ullrich A. Neuron. 1992; 9: 383-391Abstract Full Text PDF PubMed Scopus (1292) Google Scholar, 2Seedorf K. Metabolism. 1995; 44: 24-32Abstract Full Text PDF PubMed Scopus (38) Google Scholar). Binding of the ligand to the cognate growth receptors initiates a complex network of intracellular signals leading to cell growth, differentiation, and transformation (1Schlessinger J. Ullrich A. Neuron. 1992; 9: 383-391Abstract Full Text PDF PubMed Scopus (1292) Google Scholar, 2Seedorf K. Metabolism. 1995; 44: 24-32Abstract Full Text PDF PubMed Scopus (38) Google Scholar). However, growth factors do usually not initiate the various metabolic effects seen with insulin, such as increased glucose transport and GLUT4 translocation (3Robinson L.J. Razzack Z.F. Lawrence Jr., J.C. James D.E. J. Biol. Chem. 1993; 268: 26422-26427Abstract Full Text PDF PubMed Google Scholar). Following insulin binding, the insulin receptor undergoes autophosphorylation, and this event allows the propagation of signals by phosphorylation on tyrosine and, subsequently, on serine residues of several downstream signaling molecules. The insulin receptor substrates (IRSs), particularly IRS-1, are the main docking proteins in the insulin signaling pathway. They have several sites that, upon tyrosine phosphorylation, bind proteins with Src homology 2/3 (SH2/SH3) domains or adaptor proteins like the 85-kDa regulatory subunit of PI 3-kinase, SHP2/Syp, Nck, and Grb-2 (4Myers Jr., M.G. White M.F. Annu. Rev. Pharmacol. Toxicol. 1996; 36: 615-658Crossref PubMed Scopus (297) Google Scholar, 5Cheatham B. Kahn C.R. Endocr. Rev. 1995; 16: 117-142Crossref PubMed Google Scholar, 6Virkamaki A. Ueki K. Kahn C.R. J. Clin. Invest. 1999; 103: 931-943Crossref PubMed Scopus (721) Google Scholar). These proteins then transmit the further downstream signals to elicit insulin's diverse actions on metabolism and cell growth. Similar to growth factors and independent of IRS phosphorylation, insulin activates the p21ras/MAP kinase pathway through the phosphorylation and activation of Shc (7Ricketts W.A. Rose D.W. Shoelson S. Olefsky J.M. J. Biol. Chem. 1996; 271: 26165-26169Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar). The phosphorylated and activated EGF receptor (EGFR) can also recruit proteins with SH2/SH3 domains, but, in contrast to the insulin receptor, many of these proteins bind directly to the phosphorylated receptor. This leads to the activation of PI 3-kinase and tyrosine phosphorylation of cytoplasmic target proteins, which will then elicit the various biological effects of EGF. The activation of PI 3-kinase lipid kinase and the downstream serine/threonine kinase, PKB/Akt, by insulin is critical for the translocation of GLUT4 to the plasma membrane and the increased glucose transport (4Myers Jr., M.G. White M.F. Annu. Rev. Pharmacol. Toxicol. 1996; 36: 615-658Crossref PubMed Scopus (297) Google Scholar, 8Smith U. Carvalho E. Mosialou E. Beguinot F. Formisano P. Rondinone C. Biochem. Biophys. Res. Commun. 2000; 268: 315-320Crossref PubMed Scopus (58) Google Scholar, 9Hill M.M. Clark S.F. Tucker D.F. Birnbaum M.J. James D.E. Macaulay S.L. Mol. Cell. Biol. 1999; 19: 7771-7781Crossref PubMed Google Scholar, 10Kohn A.D. Summers S.A. Birnbaum M.J. Roth R.A. J. Biol. Chem. 1996; 271: 31372-31378Abstract Full Text Full Text PDF PubMed Scopus (1093) Google Scholar, 11Tanti J.F. Grillo S. Gremeaux T. Coffer P.J. Van Obberghen E. Le Marchand-Brustel Y. Endocrinology. 1997; 138: 2005-2010Crossref PubMed Google Scholar). Similar to other growth factors, it has been shown that EGF and PDGF do not increase glucose transport in 3T3-L1 and rat adipocytes (3Robinson L.J. Razzack Z.F. Lawrence Jr., J.C. James D.E. J. Biol. Chem. 1993; 268: 26422-26427Abstract Full Text PDF PubMed Google Scholar, 12Lin T.A. Lawrence Jr., J.C. J. Biol. Chem. 1994; 269: 21255-21261Abstract Full Text PDF PubMed Google Scholar,13Stagsted J. Ziebe S. Satoh S. Holman G.D. Cushman S.W. Olsson L. J. Biol. Chem. 1993; 268: 1770-1774Abstract Full Text PDF PubMed Google Scholar), whereas it has been reported that EGF can increase glucose transport in transgenic 3T3-L1 adipocytes overexpressing the EGFR (14Hardy R.W. Gupta K.B. McDonald J.M. Williford J. Wells A. Endocrinology. 1995; 136: 431-439Crossref PubMed Scopus (26) Google Scholar,15Van Epps-Fung M. Hardy R.W. Williford J. Gupta K. Wells A. Diabetes. 1996; 45: 1619-1625Crossref PubMed Scopus (11) Google Scholar). The inability of growth factors to activate glucose transport and metabolism has been attributed to the subcellular compartment where PI 3-kinase becomes activated. Growth factors, in general, activate PI 3-kinase by binding to the cognate receptors in the plasma membrane, whereas insulin uses the cytoplasmic IRS molecules, which can be targeted to the intracellular microsomal and GLUT4-containing compartment (4Myers Jr., M.G. White M.F. Annu. Rev. Pharmacol. Toxicol. 1996; 36: 615-658Crossref PubMed Scopus (297) Google Scholar, 16Inoue G. Cheatham B. Emkey R. Kahn C.R. J. Biol. Chem. 1998; 273: 11548-11555Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar). Grb2-associated binder 1 (Gab1) and the closely related protein, Gab2 (17Gu H. Pratt J.C. Burakoff S.J. Neel B.G. Mol. Cell. 1998; 2: 729-740Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar, 18Nishida K. Yoshida Y. Itoh M. Fukada T. Ohtani T. Shirogane T. Atsumi T. Takahashi-Tezuka M. Ishihara K. Hibi M. Hirano T. Blood. 1999; 93: 1809-1816Crossref PubMed Google Scholar), belong to the IRS-like family of proteins. Gab1 and Gab2 have been shown to be important mediators of the signal transduction of growth factors and cytokines (18Nishida K. Yoshida Y. Itoh M. Fukada T. Ohtani T. Shirogane T. Atsumi T. Takahashi-Tezuka M. Ishihara K. Hibi M. Hirano T. Blood. 1999; 93: 1809-1816Crossref PubMed Google Scholar, 19Wickrema A. Uddin S. Sharma A. Chen F. Alsayed Y. Ahmad S. Sawyer S.T. Krystal G., Yi, T. Nishada K. Hibi M. Hirano T. Platanias L.C. J. Biol. Chem. 1999; 274: 24469-24474Abstract Full Text Full Text PDF PubMed Scopus (88) Google Scholar). Gab1 becomes tyrosine-phosphorylated by insulin, EGF, and other growth factors in A431 cells (20Holgado-Madruga M. Emlet D.R. Moscatello D.K. Godwin A.K. Wong A.J. Nature. 1996; 379: 560-564Crossref PubMed Scopus (601) Google Scholar) and can bind the p85 subunit and activate PI 3-kinase in response to EGF in different cell lines (20Holgado-Madruga M. Emlet D.R. Moscatello D.K. Godwin A.K. Wong A.J. Nature. 1996; 379: 560-564Crossref PubMed Scopus (601) Google Scholar). In in a Gab2 was found to be the target for PI 3-kinase activation by EGF in rat M. J. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus (43) Google Scholar). In the examined the metabolic of different growth factors in human and rat fat cells. found that EGF, in contrast to other growth factors, a insulin-like in but not fat cells. This is to the of EGFR in but not also the intracellular signaling pathways for insulin, EGF and the is also a ligand for the increase the tyrosine phosphorylation and p85 binding to several intracellular docking proteins IRS-2, and leading to the activation of both the metabolic and mitogenic pathways. by activating PI 3-kinase pools that are additional to those of insulin, EGF can also augment the downstream signaling of insulin in insulin-resistant states like Type 2 diabetes. insulin was and were and and other were were 3-kinase, and were and were kinase were and were were a Cushman of of human were the of for In of the the were with Type 2 diabetes. The were in with were the in and in to The was by the of the cells were to U. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar, U. L. P. J. Res. Full Text PDF PubMed Google Scholar). The was of and of was in and in a cells were through a and in and were measured as U. L. P. J. Res. Full Text PDF PubMed Google Scholar). were then with the various as in plasma were and as U. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar, Cushman S.W. Diabetes. PubMed Scopus Google Scholar). The were in 1 and for proteins by the a of were with of on and then was as transport was for 1 with as 1 the cells were the by through and the with the cells was measured by U. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar). human adipocytes were cell in a of were with the for by through and in of 1 1 and and for 2 was by for and the were with the different to the of the the were with for The were with cell or were in for The were by or were the to and in The were with the different to the of the The proteins were by and the of the was with a The PI 3-kinase was directly on IRS-1 or Gab1 as U. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar). the of a of phosphatidylinositol and were to the The was by the addition of of a of the was by the addition of of and of The was and to a with The were in and by The was with a was to the for EGF and in fat cells and for EGFR in both fat cells and skeletal the was and for were measured as reported in J. Res. 1996; PubMed Scopus Google Scholar, E. U. J. PubMed Scopus Google Scholar). The for the and were as EGF EGF EGF EGFR EGFR EGFR of but not increased glucose transport to the as insulin, and was seen both EGF and insulin were insulin, glucose transport in response to EGF was by both and of PI 3-kinase T. Y. T. M. J. Biol. Chem. 1994; 269: Full Text PDF PubMed Google Scholar) and U. Carvalho E. Mosialou E. Beguinot F. Formisano P. Rondinone C. Biochem. Biophys. Res. 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Res. 1992; PubMed Scopus Google Scholar), also increased glucose transport to the as insulin and with a similar (EC50 ∼0.2 nm) 1 B and not In for EGF nm) was than for insulin or 1 EGF also a similar as insulin, and both effects were by 1 these that EGF lipolysis and glucose transport to the as insulin but with a the effects of both were by as well as not that were through PI 3-kinase shown in EGF increased the tyrosine phosphorylation of and whereas the insulin-stimulated were seen and The tyrosine-phosphorylated was as Gab1 by both 2 and which also activated EGFR 2 not increase the tyrosine phosphorylation of Gab1 in human fat cells. Gab1 tyrosine phosphorylation by EGF was also by that it was through PI 3-kinase activation 2 The phosphorylated by EGF were as both the EGFR and IRS-1 and 2 The ability of EGF to increase tyrosine phosphorylation of IRS-1 was and was seen 2 not further the that the activated EGFR can bind to and IRS-1, were EGFR was in IRS-1 and, EGF increased the of IRS-1 in EGFR not EGF insulin-like effects on glucose transport and lipolysis and increased the tyrosine phosphorylation of both IRS-1 and IRS-2, this was not to activation of the insulin receptor, EGF, in contrast to insulin, not increase the tyrosine phosphorylation of the insulin receptor 2 these that both EGF and insulin increase the tyrosine phosphorylation of IRS-1 and IRS-2, showing for cognate receptors, and, in EGF tyrosine phosphorylation of Gab1 through a and, thus, PI pathway. The ability of EGF, but not insulin, to and activate Gab1 is also with the that Gab1 was to the plasma membrane in response to EGF but not insulin also examined EGF increased the tyrosine phosphorylation of Gab2 or However, and on of these proteins was found not The ability of insulin and EGF to increase tyrosine phosphorylation in fat cells, where EGF not increase glucose transport or lipolysis not in with J. Ziebe S. Satoh S. Holman G.D. Cushman S.W. Olsson L. J. Biol. Chem. 1993; 268: 1770-1774Abstract Full Text PDF PubMed Google Scholar), was also In contrast to human fat cells, Gab1 IRS-1 or were phosphorylated by EGF The phosphorylated the of EGFR that rat fat cells have as also reported J. Ziebe S. Satoh S. Holman G.D. Cushman S.W. Olsson L. J. Biol. Chem. 1993; 268: 1770-1774Abstract Full Text PDF PubMed Google Scholar). examined the p85 regulatory subunit of PI 3-kinase with tyrosine-phosphorylated IRS-1, and Gab1 in response to EGF. shown in 3, EGF increased the of p85 with all of these docking proteins additional by the of insulin, whereas insulin only increased the with both insulin and EGF increased the p85 binding to not also measured PI 3-kinase in response to EGF in IRS-1 and Gab1 EGF increased PI 3-kinase with IRS-1 whereas the increase in was more not a of downstream examined the ability of EGF and/or insulin to increase the and serine phosphorylation of shown in both EGF and insulin increased the phosphorylation of to a similar In phosphorylation of kinase was more pronounced in the fat cells with EGF than with insulin The that EGF activates PI 3-kinase in pools IRS-2, and that are additional to those of insulin then EGF can be to augment insulin in insulin-resistant states by the ability of insulin or in with EGF to increase the downstream insulin signaling, measured as serine phosphorylation of PKB/Akt, in fat cells Type 2 and shown in EGF to a similar to insulin in and effects were However, insulin-stimulated is in cells Type 2 Carvalho E. C. 1999; PubMed Scopus Google Scholar, E. B. C. U. 2000; PubMed Scopus Google Scholar) where IRS-1 protein is P. C. U. U. S. A. 1997; PubMed Scopus Google Scholar). that the insulin-stimulated tyrosine phosphorylation of IRS was in cells, whereas the ability of EGF or in with insulin to increase the phosphorylation of Gab1 was This is with the that Gab1 protein was similar in and cells not The tyrosine phosphorylation of in cells is to the IRS-1 EGFR was similar in both not with the that EGF activates PI 3-kinase pools that are additional to those of insulin and that these are in cells P. C. U. U. S. A. 1997; PubMed Scopus Google Scholar), also found that the addition of EGF increased downstream insulin signaling measured as as with insulin in cells Type 2 EGF mimicked insulin, both in of the metabolic effects and downstream signaling, examined human fat cells EGF and/or for or However, found for EGF or in human fat cells for EGF, and EGFR to of was in the not The of the for the of was in a to of was in the not The of the for the of was In the EGF receptor was abundantly expressed in human fat cells as well as in skeletal the In this for the that the growth factors but not exert insulin-like effects in human fat cells and that EGF a than insulin to elicit these effects (EC50 ∼0.02 These with the of the receptor tyrosine phosphorylation by EGF as well as EGFR protein that EGF receptors are expressed in human fat cells. This is different rat fat cells, which have a of EGF receptors as also reported J. Ziebe S. Satoh S. Holman G.D. Cushman S.W. Olsson L. J. Biol. Chem. 1993; 268: 1770-1774Abstract Full Text PDF PubMed Google Scholar). This is the for the that EGF not exert insulin-like effects in rat fat cells. In EGF receptors to be more abundantly expressed in fat cells, including 3T3-L1 cells J.C. A.K. U. S. A. PubMed Scopus Google Scholar), where a insulin-like has been reported Biochem. Mol. Biol. 1995; 36: Google Scholar). In general, growth factors do not exert insulin-like effects the that increase PI 3-kinase This has been attributed to inability to activate PI 3-kinase in subcellular G. Cheatham B. Emkey R. Kahn C.R. J. Biol. Chem. 1998; 273: 11548-11555Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar, J.M. J.F. Van Obberghen E. Le Marchand-Brustel Y. J. Biochem. 1996; PubMed Scopus Google Scholar), to activation of M.M. Clark S.F. Tucker D.F. Birnbaum M.J. James D.E. Macaulay S.L. Mol. Cell. Biol. 1999; 19: 7771-7781Crossref PubMed Google Scholar, J. Birnbaum M.J. A.K. H. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar), and/or to increased serine and tyrosine phosphorylation of IRS-1 Van Obberghen E. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar). However, the that growth factors, like can exert insulin-like effects the cognate receptors are abundantly expressed with the downstream signaling molecules. The EGF receptor has sites for with substrates like IRS-1 T. M. J. Biochem. 268: PubMed Scopus Google Scholar) and The that EGF the tyrosine phosphorylation of the signaling as seen with insulin and, in Gab1 as well as cognate receptor. both insulin and EGF increase the downstream phosphorylation and activation of PKB/Akt, which to important for the insulin-stimulated glucose transport U. Carvalho E. Mosialou E. Beguinot F. Formisano P. Rondinone C. Biochem. Biophys. Res. Commun. 2000; 268: 315-320Crossref PubMed Scopus (58) Google Scholar, 9Hill M.M. Clark S.F. Tucker D.F. Birnbaum M.J. James D.E. Macaulay S.L. Mol. Cell. Biol. 1999; 19: 7771-7781Crossref PubMed Google Scholar), whereas EGF increased kinase phosphorylation to a than insulin. The that the EGFR is also abundantly expressed in human skeletal is with that EGF, similar to the in fat cells, glucose transport in to the as insulin. S. and U. These the that EGF, by of ability to activate a of docking proteins for PI 3-kinase IRS-2, and the metabolic response in insulin-resistant including Type 2 where PI 3-kinase activation and tyrosine phosphorylation of IRS-1 are in both fat cells E. U. J. PubMed Scopus Google P. C. U. U. S. A. 1997; PubMed Scopus Google Scholar) and skeletal A. H. 2000; PubMed Scopus Google Scholar). this EGF was to augment downstream insulin signaling in cells Type 2 The binding of the EGF family of for the EGFR family are different S. S. Ullrich A. Endocr. PubMed Scopus Google Scholar). which to EGFR EGF and whereas the bind to and The that both EGF and elicit the metabolic with that a kinase of the effects of EGF not that were through The phosphorylation and activation of Gab1 by EGF in human fat cells is similar to has been reported in other cells, Gab2 has also been reported to be the docking protein for PI 3-kinase activation in rat M. J. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus (43) Google Scholar). However, both Gab2 and Shc were only and inconsistently phosphorylated by EGF in human fat cells. which belongs to the insulin receptor family of adaptor (20Holgado-Madruga M. Emlet D.R. Moscatello D.K. Godwin A.K. Wong A.J. Nature. 1996; 379: 560-564Crossref PubMed Scopus (601) Google Scholar), is phosphorylated by several growth factors EGF, hepatocyte growth factor, growth factor, and cytokines and α and and and and B cell (18Nishida K. Yoshida Y. Itoh M. Fukada T. Ohtani T. Shirogane T. Atsumi T. Takahashi-Tezuka M. Ishihara K. Hibi M. Hirano T. Blood. 1999; 93: 1809-1816Crossref PubMed Google Scholar, M. Emlet D.R. Moscatello D.K. Godwin A.K. Wong A.J. Nature. 1996; 379: 560-564Crossref PubMed Scopus (601) Google M. Yoshida Y. Fukada T. Ohtani T. Y. K. K. Hibi M. Hirano T. Mol. Cell. Biol. 1998; PubMed Scopus Google Scholar, C. S. S. S. F. S. P. C. PubMed Scopus Google Scholar). this of Gab1 has been found to a critical for hepatocyte growth factor signaling, and a that is similar to that seen in hepatocyte growth factor M. H. T. J. U. C. J. Biol. 2000; PubMed Scopus Google Scholar). Gab1 was a tyrosine-phosphorylated in response to EGF in human fat cells both and Type 2 Gab1 activation is with the of several signal like PI 3-kinase, and factors to and cell growth. Gab1 in addition to IRS-1 and (4Myers Jr., M.G. White M.F. Annu. Rev. Pharmacol. Toxicol. 1996; 36: 615-658Crossref PubMed Scopus (297) Google Scholar), also can a for the insulin-like effects of EGF transport and to be However, the that this is Gab1 phosphorylation was in cells and EGF also the downstream insulin signaling in these cells. The that EGF the phosphorylation of both IRS-1 and is in with the of rat as well as A431 cells abundantly EGFR T. M. J. Biochem. 268: PubMed Scopus Google Scholar, T. H. K. M. S. M. J. Biochem. 268: PubMed Scopus Google Scholar). These reported that EGFR directly phosphorylated IRS-1 in in T. H. K. M. S. M. J. Biochem. 268: PubMed Scopus Google Scholar) and that this was the of EGFR was The human EGFR which bind to the domains of IRS-1, similar to the insulin receptor S. L.C. Biochem. 1995; Full Text PDF PubMed Scopus Google Scholar). The that the effects of EGF has not been reported and that have been reported in 3T3-L1 cells overexpressing EGFR (14Hardy R.W. Gupta K.B. McDonald J.M. Williford J. Wells A. Endocrinology. 1995; 136: 431-439Crossref PubMed Scopus (26) Google Scholar, Epps-Fung M. Hardy R.W. Williford J. Gupta K. Wells A. Diabetes. 1996; 45: 1619-1625Crossref PubMed Scopus (11) Google Scholar) is to the different cell as well as the of of EGF. phosphorylation of IRS-1 is 2 and then T. H. K. M. S. M. J. Biochem. 268: PubMed Scopus Google Scholar). In human fat cells, where EGFR is a but the tyrosine phosphorylation of IRS-1 for The tyrosine phosphorylation of IRS-1 and is to kinase of EGFR and the binding to the found for of with IRS-1 of tyrosine phosphorylation not is human fat cells a of EGFR that activate both the metabolic and pathways. human skeletal also a of a is can a in human or are the growth and of the skeletal and However, EGF has been shown to increase the growth and of cells in the of G. Biochem. Biophys. Res. Commun. PubMed Scopus Google Scholar). have found EGF to increase the growth of a human cell and U. Thus, important in growth. found that EGF or are expressed in human fat cells or skeletal a However, EGFR have a for the of EGF H. K. T. J. Clin. Invest. 1995; PubMed Scopus Google Scholar) a in glucose and lipid in and for human with the insulin receptors do not like of insulin receptors A. F. M.J. M. Y. E. R. E. H. T. Endocr. Rev. 1992; PubMed Scopus Google Scholar, Diabetes. 1992; PubMed Scopus Google Scholar). the of EGF in the are in In the that growth factors like are capable of the effects of insulin in human fat cells and that EGF receptors are abundantly expressed in both human skeletal and fat cells. EGF activates several PI 3-kinase pools IRS-2, and that are additional to those of insulin This ability it for EGF to augment the effects of insulin in insulin-resistant states like Type 2 diabetes. for with the and for