Insulin Action and Its Disturbances in Disease - part 2 pptx

46 THE INSULIN RECEPTOR AND DOWNSTREAM SIGNALLING 112. Cameron, K. E., Resnik, J. and Webster, N. J. (1992) Transcriptional regulation of the human insulin receptor gene. JBiolChem267, 17 375–17 383. 113. Brunetti, A., Foti, D. and Goldfine, I. D. (1993) Identification of unique nuclear regula- tory proteins for the insulin receptor gene, which appear during myocyte and adipocyte differentiation. J Clin Invest 92, 1288–1295. 114. Webster, N. J., Kong, Y., Cameron, K. E. and Resnik, J. L. (1994) An upstream ele- ment from the human insulin receptor gene promoter contains binding sites for C/EBP- beta and NF-1. Diabetes 43, 305–312. 115. McKeon, C., Accili, D., Chen, H., Pham, T. and Walker, G. E. (1997) A conserved region in the first intron of the insulin receptor gene binds nuclear proteins during adipocyte differentiation. Biochem Biophys Res Commun 240, 701–706. 116. Lee, J. K. and Tsai, S. Y. (1994) Multiple hormone response elements can confer glu- cocorticoid regulation on the human insulin receptor gene. Mol Endocrinol 8, 625–634. 117. Mamula, P. W., McDonald, A. R., Brunetti, A., Okabayashi, Y., Wong, K. Y., Mad- dux, B. A., Logsdon, C. and Goldfine, I. D. (1990) Regulating insulin receptor gene expression by differentiation and hormones. Diabetes Care 13, 288–301. 118. Shen, W. J., Kim, H. S. and Tsai, S. Y. (1995) Stimulation of human insulin receptor gene expression by retinoblastoma gene product. JBiolChem270, 20 525–20 529. 119. Webster, N. J., Resnik, J. L., Reichart, D. B., Strauss, B., Haas, M. and Seely, B. L. (1996) Repression of the insulin receptor promoter by the tumor suppressor gene product p53: a possible mechanism for receptor over-expression in breast cancer. Cancer Res 56, 2781–2788. 120. Giraud, S., Greco, A., Brink, M., Diaz, J. J. and Delafontaine, P. (2001) Translation initiation of the insulin-like growth factor I receptor mRNA is mediated by an internal ribosome entry site. JBiolChem276, 5668–5675. 121. Knutson, V. P., Ronnett, G. V. and Lane, M. D. (1983) Rapid, reversible internaliza- tion of cell surface insulin receptors. Correlation with insulin-induced down regulation. JBiolChem258, 12 139–12 142. 122. Thien, C. B. and Langdon, W. Y. (2001) Cbl: many adaptations to regulate protein tyrosine kinases. Nat Rev Mol Cell Biol 2, 294–307. 123. Haglund, K., Sigismund, S., Polo, S., Szymkiewicz, L., Di Fiore, P. P. and Dikic, I. (2003) Multiple monoubiquitination of RTKs is sufficient for their endocytosis and degradation. Nat Cell Biol 5, 461–466. 124. Ahmed, Z., Smith, B. J. and Pillay, T. S. (2000) The APS adapter protein couples the insulin receptor to the phosphorylation of c-Cbl and facilitates ligand-stimulated ubiq- uitination of the insulin receptor. FEBS Lett 475, 31–34. 125. Vecchione, A., Marchese, A., Henry, P., Rotin, D. and Morrione, A. (2003) The Grb10/ Nedd4 complex regulates ligand-induced ubiquitination and stability of the insulin-like growth factor I receptor. Mol Cell Biol 23, 3363–3372. 126. Helmerhorst, E. and Yip, C. (1993) Insulin binding to rat liver membranes predicts a homogeneous class of binding sites in different affinity states that may be related to a regulator of insulin binding. Biochemistry 32, 2356–2362. 127. Ramalingam, T. S., Chakrabarti, A. and Edidin, M. (1997) Interaction of class I human leukocyte antigen (HLA-I) molecules with insulin receptors and its effect on the insulin signaling cascade. Mol Biol Cell 8, 2463–2474. 128. Goldfine, I. D., Maddux, B. A., Youngren, J. F., Frittitta, L., Trischitta, V. and Dohm, G. L. (1998) Membrane glycoprotein PC-1 and insulin resistance. Mol Cell Biochem 182, 177–184. 129. Norgren, S., Zierath, J., Galuska, D., Wallberg-Henriksson, H. and Luthman, H. (1993) Differences in the ratio of RNA encoding two isoforms of the insulin receptor between REFERENCES 47 control and NIDDM patients. The RNA variant without Exon 11 predominates in both groups. Diabetes 42, 675–681. 130. Anderson, C. M., Henry, R. R., Knudson, P. E., Olefsky, J. M. and Webster, N. J. (1993) Relative expression of insulin receptor isoforms does not differ in lean, obese, and noninsulin-dependent diabetes mellitus subjects. J Clin Endocrinol Metab 76, 1380– 1382. 131. Kellerer, M., Sesti, G., Seffer, E., Obermaier-Kusser, H., Pongratz, D. E., Mosthaf, L. and Haring, H. U. (1993) Altered pattern of insulin receptor isotypes in skeletal mus- cle membranes of type 2 (non-insulin-dependent) diabetic subjects. Diabetologia 36, 628–632. 132. Hansen, T., Bjorbaek, C., Vestergaard, H., Gronskov, K., Bak, J. F. and Pedersen, O. (1993) Expression of insulin receptor spliced variants and their functional correlates in muscle from patients with non-insulin-dependent diabetes mellitus. J Clin Endocrinol Metab 77, 1500–1505. 133. Sell, S. M., Reese, D. and Ossowski, V. M. (1994) Insulin-inducible changes in insulin receptor mRNA splice variants. JBiolChem269, 30 769–30 772. 134. Savkur, R. S., Philips, A. V. and Cooper, T. A. (2001) Aberrant regulation of insulin receptor alternative splicing is associated with insulin resistance in myotonic dystrophy. Nat Genet 29, 40–47. 135. White, M. F. (1998) The IRS-signaling system: a network of docking proteins that mediate insulin and cytokine action. Rec Prog Horm Res 53, 119–138. 136. White, M. F., Maron, R. and Kahn, C. R. (1985) Insulin rapidly stimulates phosphory- lation of a Mr-185,000 protein in intact cells. Nature 318, 183–186. 137. Sun, X. J., Rothenberg, P., Kahn, C. R., Backer, J. M., Araki, E., Wilden, P. A., Cahill, D. A., Goldstein, B. J. and White, M. F. (1991) Structure of the insulin receptor sub- strate IRS-1 defines a unique signal transduction protein. Nature 352, 73–77. 138. Sun, X. J., Wang, L. M., Zhang, Y., Yenush, L., Myers, M. G., Glasheen, E., Lane, W. S., Pierce, J. H. and White, M. F. (1995) Role of IRS-2 in insulin and cytokine signalling. Nature 377, 173–177. 139. Johnston, J. A., Wang, L. M., Hanson, E. P., Sun, X. J., White, M. F., Oakes, S. A., Pierce, J. H. and O’Shea, J. J. (1995) Interleukins 2, 4, 7, and 15 stimulate tyrosine phosphorylation of insulin receptor substrates 1 and 2 in T cells. Potential role of JAK kinases. JBiolChem270, 28 527–28 530. 140. Yenush, L. and White, M. F. (1997) The IRS-signalling system during insulin and cytokine action. Bioessays 19, 491–500. 141. He, W., O’Neill, T. J. and Gustafson, T. A. (1995) Distinct modes of interaction of SHC and insulin receptor substrate-1 with the insulin receptor NPEY region via non- SH2 domains. JBiolChem270, 23 258–23 262. 142. van der Geer, P., Wiley, S. and Pawson, T. (1999) Re-engineering the target specificity of the insulin receptor by modification of a PTB domain binding site. Oncogene 18, 3071–3075. 143. Yenush, L., Makati, K. J., Smith-Hall, J., Ishibashi, O., Myers, M. G. and White, M. F. (1996) The pleckstrin homology domain is the principal link between the insulin recep- tor and IRS-1. JBiolChem271, 24 300–24 306. 144. Jacobs, A. R., LeRoith, D. and Taylor, S. I. (2001) Insulin receptor substrate-1 pleck- strin homology and phopshotyrosine-binding domains are both involved in plasma membrane targeting. JBiolChem276, 40 795–40 802. 145. Vainshtein, I., Kovacina, K. S. and Roth, R. A. (2001) The insulin receptor substrate (IRS)-1 pleckstrin homology domain functions in downstream signaling. JBiolChem 276, 8073–8078. 48 THE INSULIN RECEPTOR AND DOWNSTREAM SIGNALLING 146. Eck, M. J., Dhe-Paganon, S., Trub, T., Nolte, R. T. and Shoelson, S. E. (1996) Struc- ture of the IRS-1 PTB domain bound to the juxtamembrane region of the insulin receptor. Cell 85, 695–705. 147. Dhe-Paganon, S., Ottinger, E. A., Nolte, R. T., Eck, M. J. and Shoelson, S. E. (1999) Crystal structure of the pleckstrin homology–phosphotyrosine binding (PH-PTB) tar- geting region of insulin receptor substrate 1. Proc Natl Acad Sci USA 96, 8378–8383. 148. Razzini, G., Ingrosso, A., Brancaccio, A., Sciacchitano, S., Esposito, D. L. and Falasca, M. (2000) Different subcellular localization and phosphoinositides binding of insulin receptor substrate protein pleckstrin homology domains. Mol Endocrinol 14, 823–836. 149. Burks, D. J., Wang, J., Towery, H., Ishibashi, O., Riedel, H. and White, M. F. (1998) IRS pleckstrin homology domains bind to acidic motifs in proteins. JBiolChem273, 31 061–31 067. 150. Farhang-Fallah, J., Randhawa, V. K., Nimnual, A., Klip, A., Bar-Sagi, D. and Rozakis- Adcock, M. (2002) The pleckstrin homology (PH) domain-interacting protein couples the insulin receptor substrate 1 PH domain to insulin signaling pathways leading to mitogenesis and GLUT4 translocation. MolCellBiol22, 7325–7336. 151. Inoue, G., Cheatham, B., Emkey, R. and Kahn, C. R. (1998) Dynamics of insulin sig- naling in 3T3-L1 adipocytes. Differential compartmentation and trafficking of insulin receptor substrate (IRS)-1 and IRS-2. JBiolChem273, 11 548–11 555. 152. Clark, S. F., Molero, J. C. and James, D. E. (2000) Release of insulin receptor sub- strate proteins from an intracellular complex coincides with the development of insulin resistance. JBiolChem275, 3819–3826. 153. Araki, E., Lipes, M. A., Patti, M. E., Bruning, J. C., Haag, B., Johnson, R. S. and Kahn, C. R. (1994) Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. Nature 372, 186–190. 154. Tamemoto, H., Kadowaki, T., Tobe, K., Yagi, T., Sakura, H., Hayakawa, T., Terauchi, Y., Ueki, K., Kaburagi, Y., Satoh, S., Hisahiko, S., Yoshioka, S., Horikoshi, H., Furuta, Y., Ikawa, Y., Kasuga, M., Yazaki, Y. and Aizawa, S. (1994) Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1. Nature 372, 182–186. 155. Bruning, J. C., Winnay, J., Bonner-Weir, S., Taylor, S. I., Accili, D. and Kahn, C. R. (1997) Development of a novel polygenic model of NIDDM in mice heterozygous for IR and IRS-1 null alleles. Cell 88, 561–572. 156. Withers, D. J., Gutierrez, J. S., Towery, H., Burks, D. J., Ren, J. M., Previs, S., Zhang, Y., Bernal, D., Pons, S., Shulman, G. I., Bonner-Weirt, S. and White, M. F. (1998) Dis- ruption of IRS-2 causes type 2 diabetes in mice. Nature 391, 900–904. 157. Kido, Y., Burks, D. J., Withers, D., Bruning, J. C., Kahn, C. R., White, M. F. and Accili, D. (2000) Tissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1 and IRS-2. J Clin Invest 105, 199–205. 158. Burks, D. J., Font de Mora, J., Schubert, M., Withers, D. J., Myers, M. J., Tow- ery, H. H., Altamuro, S. L., Flint, C. L. and White, M. F. (2000) IRS-2 pathways inte- grate female reproduction and energy homeostasis. Nature 407, 377–382. 159. Br ¨ uning, J. C., Winnay, J., Cheatham, B. and Kahn, C. R. (1997) Differential signaling by insulin receptor substrate 1 (IRS-1) and IRS-2 in IRS-1-deficient cells. Mol Cell Biol 17, 1513–1521. 160. Lavan, B. E., Lane, W. S. and Lienhard, G. E. (1997) The 60-kDa phosphotyrosine protein in insulin-treated adipocytes is a new member of the insulin receptor substrate family. JBiolChem272, 11 439–11 443. 161. Bj ¨ ornholm, M., He, A. R., Attersand, A., Lake, S., Liu, S. C. H., Lienhard, G. E., Taylor, S., Arner, P. and Zierath, J. R. (2002) Absence of functional insulin receptor substrate-3 (IRS-3 ) gene in humans. Diabetologia 45, 1697–1702. REFERENCES 49 162. Liu, S. C., Wang, Q., Lienhard, G. E. and Keller, S. R. (1999) Insulin receptor substrate 3 is not essential for growth or glucose homeostasis. JBiolChem274, 18 093–18 099. 163. Laustsen, P. G., Michael, M. D., E. C. B., Cohen, S. E., Ueki, K., Kulkarni, R. N., Keller, S. R., Lienhard, G. E. and Kahn, C. R. (2002) Lipoatrophic diabetes in Irs1(−/−)/Irs3(−/−) double knockout mice. Genes Dev 16, 3213–3222. 164. Lavan, B. E., Fantin, V. R., Chang, E. T., Lane, W. S., Keller, S. R. and Lien- hard, G. E. (1997) A novel 160-kDa phosphotyrosine protein in insulin-treated embry- onic kidney cells is a new member of the insulin receptor substrate family. JBiolChem 272, 21 403–21 407. 165. Fantin, V. R., Wang, Q., Lienhard, G. E. and Keller, S. R. (2000) Mice lacking insulin receptor substrate 4 exhibit mild defects in growth, reproduction and glucose homeostasis. Am J Physiol Endocrinol Metab 278, E127–E133. 166. Zick, Y. (2001) Insulin resistance: a phosphorylation based uncoupling of insulin signaling. Trends Biochem Sci 11, 437–441. 167. Le Marchand-Brustel, Y., Gual, P., Gr ´ emeaux, T., Gonzalez, T., Barres, R. and Tanti, J F. (2003) Fatty acid-induced insulin resistance: role of insulin receptor substrate 1 serine phosphorylation in the retroregulation of insulin signalling. Biochem Soc Trans 31, 1152–1156. 168. Schmitz-Peiffer, C. and Whitehead, J. P. (2003) IRS-1 regulation in health and disease. IUBMB Life 55, 367–374. 169. Johnston, A. M., Pirola, L. and Van Obberghen, E. (2003) Molecular mechanisms of insulin receptor substrate protein-mediated modulation of insulin signalling. FEBS Lett 546, 32–36. 170. Greene, M. W. and Garofalo, R. S. (2002) Positive and negative regulatory roles of insulin receptor substrate 1 and 2 (IRS-1 and IRS-2) serine/threonine phosphorylation. Biochemistry 41, 7082–7091. 171. Paz, K., Liu, Y. F., DShorer, H., Hemi, R., LeRoith, D., Quan, M., Kanety, H., Seger, R. and Zick, Y. (1999) Phosphorylation of insulin receptor substrate-1 (IRS-1) by protein kinase B positively regulates IRS-1 function. JBiolChem274, 28 816–28 822. 172. Jakobsen, S. N., Hardie, D. G., Morrice, N. and Tornqvist, H. (2001) 5  -AMP-activated protein kinase phosphorylates IRS-1 on Ser-789 in mouse C2C12 myotubes in response to 5-aminoimidazole-4-carboxamide riboside. JBiolChem276, 46 912–46 916. 173. Giraud, J., Leshan, R., Lee, Y. H., and White, M. F. (2004) Nutrient-dependent and insulin-stimulated phosphorylation of insulin receptor substrate-1 on serine 302 correlates with increased insulin signaling. JBiolChem279, 3447–3454. 174. Ogihara, T., Isobe, T., Ichimura, T., Taoka, M., Funaki, M., Sakoda, H., Onishi, Y., Inukai, K., Anai, M., Fukushima, Y., Kikuchi, M., Yazaki, Y., Oka, Y. and Asano, T. (1997) 14–3–3 protein binds to insulin receptor substrate-1, one of the binding sites of which is in the phosphotyrosine binding domain. JBiolChem272, 25 267–25 274. 175. Kosaki, A., Yamada, K., Suga, J., Otaka, A. and Kuzuya, H. (1998) 14–3–3beta protein associates with insulin receptor substrate 1 and decreases insulin-stimulated phosphatidylinositol 3  -kinase activity in 3T3L1 adipocytes. JBiolChem273, 940–944. 176. Xiang, X., Yuan, M., Song, Y., Ruderman, N., Wen, R. and Luo, Z. (2002) 14–3–3 facilitates insulin-stimulated intracellular trafficking of insulin receptor substrate 1. Mol Endocrinol 16, 552–562. 177. Rui, L., Yuan, M., Frantz, D., Shoelson, S. and White, M. F. (2002) SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS-1 and IRS-2. JBiolChem277, 42 394–42 398. 178. White, M. F. (1997) The insulin signalling system and the IRS proteins. Diabetologia 40 (Suppl 2), S2–17. 50 THE INSULIN RECEPTOR AND DOWNSTREAM SIGNALLING 179. Mothe, I. and Van Obberghen, E. (1996) Phosphorylation of insulin receptor substrate-1 on multiple serine residues, 612, 632, 662, and 731, modulates insulin action. JBiol Chem 271, 11 222–11 227. 180. De Fea, K. and Roth, R. A. (1997) Protein kinase C modulation of insulin receptor substrate-1 tyrosine phosphorylation requires serine 612. Biochemistry 36, 12 939–12 947. 181. De Fea, K. and Roth, R. A. (1997) Modulation of insulin receptor substrate-1 tyrosine phosphorylation and function by mitogen-activated protein kinase. JBiolChem272, 31 400–31 406. 182. Paz, K., Hemi, R., LeRoith, D., Karasik, A., Elhanany, E., Kanety, H. and Zick, Y. (1997) A molecular basis for insulin resistance: elevated serine/threonine phosphorylation of IRS-1 and IRS-2 inhibits their binding to the juxtamembrane region of the insulin receptor and impairs their ability to undergo insulin-induced tyrosine phosphorylation. JBiolChem272, 29 911–29 918. 183. Aguirre, V., Werner, E. D., Giraud, J., Lee, Y. H., Shoelson, S. E. and White, M. F. (2002) Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action. JBiolChem277, 1531–1537. 184. Haruta, T., Uno, T., Kawahara, J., Takano, A., Egawa, K., Sharma, P. M., Olef- sky, J. M. and Kobayashi, M. (2000) A rapamycin-sensitive pathway down-regulates insulin signaling via phosphorylation and proteasomal degradation of insulin receptor substrate-1. Mol Endocrinol 14, 783–794. 185. Takano, A., Usui, I., Haruta, T., Kawahara, J., Uno, T., Iwata, M. and Kobayashi, M. (2001) Mammalian target of rapamycin pathway regulates insulin signaling via subcellular redistribution of insulin receptor substrate 1 and integrates nutritional signals and metabolic signals of insulin. Mol Cell Biol 21, 5050–5062. 186. Greene, M. W., Sakaue, H., Wang, L., Alessi, D. R. and Roth, R. A. (2003) Modulation of insulin-stimulated degradation of human insulin receptor substrate-1 by serine 312 phosphorylation. JBiolChem278, 8199–8211. 187. Gual, P., Gremeaux, T., Gonzalez, T., Le Marchand-Brustel, Y. and Tanti, J. F. (2003) MAP kinases and mTOR mediate insulin-induced phosphorylation of insulin receptor substrate-1 on serine residues 307, 612 and 632. Diabetologia 46, 1532–1542. 188. Aguirre, V., Uchida, T., Yenush, L., Davis, R. and White, M. F. (2000) The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307). JBiolChem275, 9047–9054. 189. Rui, L., Aguirre, V., Kim, J., Shulman, G. I., Lee, A., Corbould, A., Dunaif, A. and White, M. F. (2001) Insulin/IGF-1 and TNF-alpha stimulate phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways. J Clin Invest 107, 181–189. 190. Kim, J. K., Kim, Y. J., Fillmore, J. J., Chen, Y., Moore, I., Lee, J., Yuan, M., Li, Z. W., Karin, M., Perret, P., Shoelson, S. E. and Shulman, G. I. (2001) Prevention of fat-induced insulin resistance by salicylate. J Clin Invest 108, 437–446. 191. Yu, C., Chen, Y., Zhong, H., Wang, Y., Bergeron, R., Kim, J. K., Cline, G. W., Cushman, S. W., Cooney, G. J., Atcheson, B., White, M. F., Kraegen, E. W. and Shulman, G. I. (2002) Mechanism by which fatty acids inhibit insulin activation of IRS-1 associated phosphatidylinositol 3-kinase activity in muscle. JBiolChem277, 50 230–50 236. 192. Lee, Y. H., Giraud, J., Davis, R. J. and White, M. F. (2003) c-Jun N-terminal kinase (JNK) mediates feedback inhibition of the insulin signaling cascade. JBiolChem278, 2896–2902. 193. Kanety, H., Feinstein, R., Papa, M. Z., Hemi, R. and Karasik, A. (1995) Tumor necrosis factor alpha-induced phosphorylation of insulin receptor substrate-1 (IRS-1). REFERENCES 51 Possible mechanism for suppression of insulin-stimulated tyrosine phosphorylation of IRS-1. JBiolChem270, 23 780–23 784. 194. Hotamisligil, G. S., Peraldi, P., Budavari, A., Ellis, R., White, M. F. and Spiegel- man, B. M. (1996) IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-alpha- and obesity-induced insulin resistance. Science 271, 665–668. 195. Shulman, G. I. (2000) Cellular mechanisms of insulin resistance. J Clin Invest 106, 171–176. 196. Bouzakri, K., Roques, M., Gual, P., Espinosa, S., Guebre-Egziabher, F., Riou, J. P., Laville, M., Le Marchand-Brustel, Y., Tanti, J. F. and Vidal, H. (2003) Reduced activation of phosphatidylinositol 3-kinase and increased serine 636 phosphorylation of insulin receptor substrate-1 in primary culture of skeletal muscle cells from patients with type 2 diabetes. Diabetes 52, 1319–1325. 197. Cai, D., Dhe-Paganon, S., Melendez, P. A., Lee, J. and Shoelson, S. E. (2003) Two new substrates in insulin signaling, IRS5/DOK4 and IRS6/DOK5. JBiolChem278, 25 323–25 330. 198. Liu, Y. and Rohrschneider, L. R. (2002) The gift of Gab. FEBS Lett 515, 1–7. 199. Holdago-Madruga, M., Emlet, D. R., Moscatello, D. K., Godwin, A. K. and Wong, A. J. (1996) A Grb2-associated docking protein in EGF- and insulin-receptor signalling. Nature 379, 560–563. 200. Rocchi, S., Tartare-Deckert, S., Murdaca, J., Holdago-Madruga, M., Wong, A. J. and Van Obberghen, E. (1998) Determination of Gab1 (Grb2-associated binder-1) interaction with insulin receptor-signaling molecules. Mol Endocrinol 12, 914–923. 201. Lehr, S., Kotzka, J., Herkner, A., Sikmann, A., Meyer, H. E., Krone, W. and Muller- Wieland, D. (2000) Identification of major tyrosine phosphorylation sites in the human insulin receptor substrate Gab-1 by insulin receptor kinase in vitro. Biochemistry 39, 10 898–10 907. 202. Winnay, J. N., Br ¨ uning, J. C., Burks, D. J. and Kahn, C. R. (2000) Gab-1-mediated IGF-1 signaling in IRS-1-deficient 3T3-fibroblasts. JBiolChem275, 10 545–10 550. 203. Harada, S., Esch, G. L., Holdago-Madruga, M. and Wong, A. J. (2001) Grb-2- associated binder-1 is involved in insulin-induced egr-1 gene expression through its phosphatidylinositol 3  -kinase binding site. DNA Cell Biol 20, 223–229. 204. Pelicci, G., Lanfrancone, L., Grignani, F., McGlade, J., Fomi, G., Nicoletti, I., Pawson, T. and Pelicci, P. G. (1992) A novel transforming protein (SHC) with an SH2 domain is implicated in mitogenic signal transduction. Cell 70, 93–104. 205. Pronk, G. J., McGlade, J., Pelicci, G., Pawson, T. and Bos, J. L. (1993) Insulin-induced phosphorylation of the 46- and 52-kDa Shc proteins. JBiolChem268, 5748–5753. 206. Kovacina, K. S. and Roth, R. A. (1993) Identification of SHC as a substrate of the insulin receptor kinase distinct from the GAP-associated 62 kDa tyrosine phosphoprotein. Biochem Biophys Res Commun 192, 1303–1311. 207. Sasaoka, T. and Kobayashi, M. (2000) The functional significance of Shc in insulin signalling as a substrate of the insulin receptor. Endocr J 47, 373–381. 208. Luzi, L., Confalonieri, S., Di Fiore, P. P. and Pelicci, P. G. (2000) Evolution of Shc functions from nematode to human. Curr Opin Genet Dev 10, 668–674. 209. Ravichandran, K. S. (2001) Signaling via Shc family adapter proteins. Oncogene 20, 6322–6330. 210. van der Geer, P., Wiley, S., Gish, G. D. and Pawson, T. (1996) The Shc adaptor protein is highly phosphorylated at conserved, twin tyrosine residues (Y239/240) that mediate protein–protein interactions. Curr Biol 6, 1435–1444. 211. Ishihara, H., Sasaoka, T., Wada, T., Ishiki, M., Haruta, T., Usui, I., Iwata, M., Takano, A., Uno, T., Ueno, E. and Kobayashi, M. (1998) Relative involvement of Shc tyrosine residues 239/240 and tyrosine 317 on insulin-induced mitogenic signaling 52 THE INSULIN RECEPTOR AND DOWNSTREAM SIGNALLING in rat1 fibroblasts expressing insulin receptors. Biochem Biophy Res Commun 252, 139–144. 212. Migliaccio, E., Mele, S., Salcini, A. E., Pelicci, G., Lai, K M. V., Superti-Furga, G., Pawson, T., DiFiore, P. P., Lanfrancone, L. and Pelicci, P. G. (1997) Opposite effects of the p52shc/p46shc and p66shc splicing iosforms in the EGF receptor–MAP kinase–fos signalling pathway. EMBO J 16, 706–716. 213. Okada, S., Kao, A. W., Ceresa, B. P., Blaikie, P., Margolis, B. and Pessin, J. E. (1997) The 66-kDa Shc isoform is a negative regulator of the epidermal growth factor- stimulated mitogen-activated protein kinase pathway. JBiolChem272, 28 042–28 049. 214. Kao, A. W., Waters, S. B., Okada, S. and Pessin, J. E. (1997) Insulin stimulates the phosphorylation of the 66- and 52-kilodalton Shc isoforms by distinct pathways. Endocrinology 138, 2472–2480. 215. Skolnik, E., Lee, C. H., Batzer, A., Vicentini, L. M., Zhou, M., Daly, R., Myers, M. J., Backer, J. M., Ullrich, A. and White, M. F. (1993) The SH2/SH3 domain-containing protein GRB2 interacts with tyrosine-phosphorylated IRS1 and Shc: implications for insulin control of ras signalling. EMBO J 12, 1929–1936. 216. Myers, M. G., Wang, L. M., Sun, X. J., Zhang, Y., Yenush, L., Schlessinger, J., Pierce, J. H. and White, M. F. (1994) Role of IRS-1-GRB-2 complexes in insulin signaling. Mol Cell Biol 14, 3577–3587. 217. Sasaoka, T., Draznin, B., Leitner, J. W., Langlois, W. J. and Olefsky, J. M. (1994) Shc is the predominant signaling molecule coupling insulin receptors to activation of guanine nucleotide releasing factor and p21ras-GTP formation. JBiolChem269, 10 734–10 738. 218. Valentinis, B., Romano, G., Peruzzi, F., Morrione, A., Prisco, M., Soddu, S., Cristo- fanelli, B., Sacchi, A. and Baserga, R. (1999) Growth and differentiation signals by the insulin-like growth factor 1 receptor in hemopoietic cells are mediated through different pathways. JBiolChem274, 12 423–12 430. 219. Sasaoka, T., Ishiki, M., Wada, T., Hori, H., Hirai, H., Haruta, T., Ishihara, H. and Kobayashi, M. (2001) Tyrosine phosphorylation-dependent and -independent role of Shc in the regulation of IGF-1-induced mitogenesis and glycogen synthesis. Endocrinology 142, 5226–5235. 220. Poy, N. M., Ruch, R. J., Fernstrom, M. A., Okabayashi, Y. and Najjar, S. M. (2002) Shc and CEACAM1 interact to regulate the mitogenic action of insulin. JBiolChem 277, 1076–1084. 221. Emanuelli, B., Peraldi, P., Filloux, C., Sawka-Verhelle, D., Hilton, D. and Van Obberghen, E. (2000) SOCS-3 is an insulin-induced negative regulator of insulin signaling. JBiolChem275, 15 985–15 991. 222. Ahmed, Z. and Pillay, T. S. (2001) Functional effects of APS and SH2-B on insulin receptor signalling. Biochem Soc Trans 29, 529–534. 223. Kotani, K., Wilden, P. and Pillay, T. S. (1998) SH2-Bα is an insulin-receptor adapter protein and substrate that interacts with the activation loop of the insulin-receptor kinase. Biochem J 335, 103–109. 224. Ahmed, A., Smith, B. J., Kotani, K., Wilden, P. and Pillay, T. S. (1999) APS, an adapter protein with a PH and SH2 domain, is a substrate for the insulin receptor kinase. Biochem J 341, 665–668. 225. Moodie, S. A., Alleman-Sposeto, J. and Gustafson, T. A. (1999) Identification of the APS protein as a novel insulin receptor substrate. JBiolChem274, 11 186–11 193. 226. Ahmed, Z. and Pillay, T. S. (2003) Adapter protein with a pleckstrin homology (PH) and an Src homology 2 (SH2) domain (APS) and SH2-B enhance insulin-receptor autophosphorylation, extracellular-signal-regulated kinase and phosphoinositide 3- kinase-dependent signalling. Biochem J 371, 405–412. REFERENCES 53 227. Riedel, H., Yousaf, N., Zhao, Y., Dai, H., Deng, Y. and Wang, J. (2000) PSM, a mediator of PDGF-BB-, IGF-I- and insulin-stimulated mitogenesis. Oncogene 19, 39–50. 228. Yousaf, N., Deng, Y., Kang, Y. and Riedel, H. (2001) Four PSM/SH2-B alternative splice variants and their differential roles in mitogenesis. JBiolChem276, 40 940–40 948. 229. Liu, J., Kimura, A., Baumann, C. A. and Saltiel, A. R. (2002) APS facilitates c-Cbl tyrosine phosphorylation and GLUT4 translocation in response to insulin in 3T3-L1 adipocytes. Mol Cell Biol 22, 3599–3609. 230. Minami, A., Iseki, M., Kishi, K., Wang, M., Ogura, M., Furukawa, N., Hayashi, S., Yamada, M., Obata, T., Takeshita, Y., Nakaya, Y., Bando, Y., Izumi, K., Moodie, S. A., Kajiura, F., Matsumoto, M., Takatsu, K., Takaki, S. and Ebina, Y. (2003) Increased insulin sensitivity and hypoinsulinaemia in APS knockout mice. Diabetes 52, 2657–2665. 231. Ohtsuka, S., Takaki, S., Iseki, M., Miyoshi, K., Nakagata, N., Kataoka, Y., Yoshida, N., Takatsu, K. and Yoshimura, A. (2002) SH2-B is required for both male and female reproduction. Mol Cell Biol 22, 3066–3077. 232. Daly, R. J. (1998) The Grb7 family of signalling proteins. Cell Signal 10, 613–618. 233. Han, D. C., Shen, T. L. and Guan, J. L. (2001) The Grb7 family proteins: structure, interactions with other signaling molecules and potential cellular functions. Oncogene 20, 6315–6321. 234. Morrione, A. (2003) Grb10 adapter protein as a regulator of insulin-like growth factor signaling. J Cell Physiol 197, 307–311. 235. Langlais, P., Dong, L. Q., Hu, D. and Liu, F. (2000) Identification of Grb10 as a direct substrate for members of the Src tyrosine kinase family. Oncogene 2000, 2895–2903. 236. O’Neill, T. J., Rose, D. W., Pillay, T. S., Hotta, K., Olefsky, J. M. and Gustafson, T. A. (1996) Interaction of a Grb-IR splice variant (a human Grb10 homolog) with the insulin and insulin-like growth factor-I receptors. Evidence for a role in mitogenic signaling. JBiolChem271, 22 506–22 513. 237. Laviola, L., Giorgino, F., Chow, J. C., Baquero, J. A., Hansen, H., Ooi, J., Zhu, J., Riedel, H. and Smith, R. J. (1997) The adapter protein Grb10 associates preferentially with the insulin receptor as compared with the IGF-I receptor in mouse fibroblasts. J Clin Invest 99, 830–837. 238. He, W., Rose, D. W., Olefsky, J. M. and Gustafson, T. A. (1998) Grb10 interacts differentially with the insulin receptor, insulin-like growth factor I receptor, and epidermal growth factor receptor via the Grb10 Src homology 2 (SH2) domain and a second novel domain located between the pleckstrin homology and SH2 domains. J Biol Chem 273, 6860–6867. 239. Hemming, R., Agatep, R., Badiani, K., Wyant, K., Arthur, G., Gietz, R. D. and Triggs- Raine, B. (2001) Human growth factor receptor bound 14 binds the activated insulin receptor and alters the insulin-stimulated tyrosine phosphorylation levels of multiple proteins. Biochem Cell Biol 79, 21–32. 240. Bereziat, V., Kasus-Jacobi, A., Perdereau, D., Cariou, B., Girard, J. and Burnol, A. F. (2002) Inhibition of insulin receptor catalytic activity by the molecular adapter Grb14. JBiolChem277, 4845–4852. 241. Wick, K. R., Werner, E. D., Langlais, P., Ramos, F. J., Dong, L. O., Shoelson, S. E. and Liu, F. (2003) Grb10 inhibits insulin-stimulated insulin receptor substrate (IRS)- phosphatidylinositol 3-kinase/Akt signaling pathway by disrupting the association of IRS-1/IRS-2 with the insulin receptor. JBiolChem278, 8460–8467. 242. Wang, J., Dai, H., Yousaf, N., Moussaif, M., Deng, Y., Boufelliga, A., Swamy, O. R., Leone, M. E. and Riedel, H. (1999) Grb10, a positive, stimulatory signaling adapter in 54 THE INSULIN RECEPTOR AND DOWNSTREAM SIGNALLING platelet-derived growth factor BB-, insulin-like growth factor I- and insulin-mediated mitogenesis. MolCellBiol19, 6217–6228. 243. Deng, Y., Bhattacharya, S., Swamy, O. R., Tandon, R., Wang, Y., Janda, R. and Riedel, H. (2003) Growth factor receptor-binding protein 10 (Grb10) as a partner of phosphatidylinositol 3-kinase in metabolic insulin action. JBiolChem278, 39 311–39 322. 244. Nantel, A., Mohammad-Ali, K., Sherk, J., Bosner, B. I. and Thomas, D. Y. (1998) Interaction of the Grb10 adapter protein with the Raf1 and MEK1 kinases. JBiol Chem 273, 10 475–10 484. 245. Jahn, T., Seipel, P., Urschel, S., Peschel, C. and Duyster, J. (2002) Role for the adaptor protein Grb10 in the activation of Akt. Mol Cell Biol 22, 979–991. 246. Giovannone, B., Lee, E., Laviola, L., Giorgino, F., Cleveland, K. A. and Smith, R. J. (2003) Two novel proteins that are linked to insulin-like growth factor (IGF-I) receptors by the Grb10 adaptor and modulate IGF-I signalling. JBiolChem278, 31 564–31 573. 247. Blagitko, N., Mergenthaler, S., Schulz, U., Wollmann, H. A., Craigen, W., Egger- mann, T., Ropers, H. H. and Kalscheuer, V. M. (2000) Human GRB10 is imprinted and expressed from the paternal and maternal allele in a highly tissue- and isoform-specific fashion. Hum Mol Genet 9, 1587–1595. 248. Miyoshi, N., Kuroiwa, Y., Kohda, T., Shitara, H., Yonekawa, H., Kawabe, T., Hasegawa, H., Barton, S. C., Surani, M. A., Kaneko-Ishino, T. and Ishino, F. (1998) Identification of the Meg1/Grb10 imprinted gene on mouse proximal chromosome 11, a candidate for the Silver–Russell syndrome gene. Proc Natl Acad Sci USA 95, 1102–1107. 249. Charalambous, M., Smith, F. M., Bennett, W. R., Crew, T. E., Mackenzie, F. and Ward, A. (2003) Disruption of the imprinted Grb10 gene leads to disproportionate overgrowth by an Igf2-independent mechanism. Proc Natl Acad Sci USA 100, 8292–8297. 250. Cooney, G. J., Lyons, R. J., Crew, A. J., Jensen, T. E., Molero, J. C., Mitchell, C. J., Biden, T. J., Ormandy, C. J., James, D. E. and Daly, R. J. (2004) Improved glucose homeostasis and enhanced insulin signalling in Grb14-deficient mice. EMBO J 23, 582–593. 251. Alessi, D. R. and Downes, C. P. (1998) The role of PI 3-kinase in insulin action. Biochim Biophys Acta 1436, 151–164. 252. Shepherd, P. R., Withers, D. J. and Siddle, K. (1998) Phosphoinositide 3-kinase: the key switch mechanism in insulin signalling. Biochem J 333, 471–490. 253. Cantrell, D. A. (2001) Phosphoinositide 3-kinase signalling pathways. J Cell Sci 114, 1439–1445. 254. Katso, R., Okkenhaug, K., Ahmadi, K., White, S., Timms, J. and Waterfield, M. D. (2001) Cellular function of phosphoinositide 3-kinases: implications for development, immunity, homeostasis and cancer. Annu Rev Cell Dev Biol 17, 615–675. 255. Cantley, L. C. (2002) The phosphoinositide 3-kinase pathway. Science 296, 1655–1657. 256. Dhand, R., Hiles, I., Panayotou, G., Roche, S., Fry, M. J., Gout, I., Totty, N. F., Truong, O., Vicendo, P. and Yonezawa, K. (1994) PI 3-kinase is a dual specificity enzyme: autoregulation by an intrinsic protein-serine kinase activity. EMBO J 13, 522–533. 257. Tanti, J. F., Gremeaux, T., Van Obberghen, E. and Le Marchand-Brustel, Y. (1994) Insulin receptor substrate 1 is phosphorylated by the serine kinase activity of phosphatidylinositol 3-kinase. Biochem J 304, 17–21. REFERENCES 55 258. Lam, K., Carpenter, C. L., Ruderman, N. B., Friel, J. C. and Kelly, K. L. (1994) The phosphatidylinositol 3-kinase serine kinase phosphorylates IRS-1. Stimulation by insulin and inhibition by wortmannin. JBiolChem269, 20 648–20 652. 259. Beeton, C. A., Chance, E. M., Foukas, L. C. and Shepherd, P. R. (2000) Comparison of the kinetic properties of the lipid- and protein-kinase activities of the p110alpha and p110beta catalytic subunits of class-Ia phosphoinositide 3-kinases. Biochem J 350, 353–359. 260. Lefai, E., Roques, M., Vega, N., Laville, M. and Vidal, H. (2001) Expression of the splice variants of the p85alpha regulatory subunit of phosphoinositide 3-kinase in muscle and adipose tissue of healthy subjects and type 2 diabetic patients. Biochem J 360, 117–125. 261. Terauchi, Y., Tsuji, Y., Satoh, S., Minoura, H., Murakami, K., Okuno, A., Inukai, K., Asano, T., Kaburagi, Y., Ueki, K., Nakajima, H., Hanafusa, T., Matsuzawa, Y., Sekihara, H., Yin, Y., Barrett, J. C., Oda, H., Ishikawa, H., Akanuma, Y., Komuro, I., Suzuki, M., Yamamura, K., Kodama, T., suzuki, H., Koyasu, S., Aizawa, S., Tobe, K., Fukui, Y., Yazaki, Y. and Kadowaki, T. (1999) Increased insulin sensitivity and hypoglycaemia in mice lacking the p85alpha subunit of phosphoinositide 3-kinase. Nat Genet 21, 230–235. 262. Ueki, K., Yballe, C. M., Brachmann, S. M., Vincent, D., Watt, J. M., Kahn, C. R. and Cantley, L. C. (2001) Increased insulin sensitivity in mice lacking p85beta subunit of phosphoinositide 3-kinase. Proc Natl Acad Sci USA 99, 419–424. 263. Mauvais-Jarvis, F., Ueki, K., Fruman, D. A., Hirshman, M. F., Sakamoto, K., Good- year, L. J., Iannacone, M., Accili, D., Cantley, L. C. and Kahn, C. R. (2002) Reduced expression of the murine p85alpha subunit of phosphoinositide 3-kinase improves insulin signaling and ameliorates diabetes. J Clin Invest 109, 141–149. 264. Chen, D., Mauvais-Jarvis, F., Bluher, M., Fisher, S. J., Jozsi, A., Goodyear, L. J., Ueki, K. and Kahn, C. R. (2004) p50alpha/p55alpha phosphoinositide 3-kinase knockout mice exhibit enhanced insulin sensitivity. Mol Cell Biol 24, 320–329. 265. Ueki, K., Fruman, D. A., Yballe, C. M., Fassaur, M., Klein, J., Asano, T., Cant- ley, L. C. and Kahn, C. R. (2003) Positive and negative roles of p85alpha and p85beta regulatory subunits of phosphoinositide 3-kinase in insulin signaling. JBiolChem278, 48 453–48 466. 266. Oatey, P. B., Venkateswarlu, K., Williams, A. G., Fletcher, L. M., Foulstone, E. J., Cullen, P. J. and Tavare, J. M. (1999) Confocal imaging of the subcellular distribution of phosphatidylinositol 3,4,5-trisphosphate in insulin- and PDGF-stimulated 3T3-L1 adipocytes. Biochem J 344, 511–518. 267. Heller-Harrison, R. A., Morin, M., Guilherme, A. and Czech, M. P. (1996) Insulin- mediated targeting of phosphatidylinositol 3-kinase to GLUT4-containing vesicles. J Biol Chem 271, 10 200–10 204. 268. Leslie, N. R. and Downes, C. P. (2002) PTEN: the down side of PI 3-kinase signalling. Cell Signal 14, 285–295. 269. Ono, H., Katagiri, H., Funaki, M., Anai, M., Inukai, K., Fukushima, Y., Sakoda, H., Ogihara, T., Onishi, Y., Fujishiro, M., Kikuchi, M., Oka, Y. and Asano, T. (2001) Regulation of phosphoinositide metabolism, Akt phosphorylation, and glucose transport by PTEN (phosphatase and tensin homolog deleted on chromosome 10) in 3T3-L1 adipocytes. Mol Endocrinol 15, 1411–1422. 270. Wada, T., Sasaoka, T., Funaki, M., Hori, H., Murakami, S., Ishiki, M., Haruta, T., Asano, T., Ogawa, W., Ishihara, H. and Kobayashi, M. (2001) Overexpression of SH2- containing inositol phosphatase 2 results in negative regulation of insulin-induced metabolic actions in 3T3-L1 adipocytes via its 5  -phosphatase catalytic activity. Mol Cell Biol 21, 1633–1646. [...]... 115, 28 57 28 66 29 0 Calera, M R., Martinez, C., Liu, H., Jack, A K., Birnbaum, M J and Pilch, P F (1998) Insulin increases the association of Akt -2 with Glut4-containing vesicles J Biol Chem 27 3, 720 1– 720 4 REFERENCES 57 29 1 Kupriyanova, T A and Kandror, K V (1999) Akt -2 binds to Glut4-containing vesicles and phosphorylates their component proteins in response to insulin J Biol Chem 27 4, 1458–1564 29 2... 914 363 Ogawa, W., Matozaki, T and Kasuga, M (1998) Role of binding proteins to IRS-1 in insulin signalling Mol Cell Biochem 1 82, 13 22 364 Fukunaga, K., Noguchi, T., Takeda, H., Matozaki, T., Hayashi, Y., Itoh, H and Kasuga, M (20 00) Requirement for protein tyrosine phosphatase SHP -2 in insulininduced activation of c-Jun NH (2) -terminal kinase J Biol Chem 27 5, 520 8– 521 3 365 Maegawa, H., Hasegawa, M.,... lacking insulin receptors in β-cells manifest impaired glucose-mediated insulin secretion Conversely, mice in which the insulin receptor was ablated in neuronal cells exhibit elevated food intake and diet-induced obesity, suggesting that insulin delivers an anorexogenic input to the central nervous system .23 Such a role of insulin in the brain was suggested in early studies where the hormone was administered... 3-phosphoinositide-dependent protein kinase-1 and its target threonine410 in the activation loop of protein kinase C-zeta Mol Endocrinol 13, 1766–17 72 Imamura, T., Huang, J., Usui, I., Satoh, H., Bever, J and Olefsky, J M (20 03) Insulininduced GLUT4 translocation involves protein kinase C-lambda-mediated functional coupling between Rab4 and the motor protein kinesin Mol Cell Biol 23 , 48 92 4900 Matsumoto,... transduction in insulin action Bioessays 23 , 21 5 22 2 Chunqiu Hou, J and Pessin, J E (20 03) Lipid raft targeting of the TC10 amino terminal domain is responsible for disruption of adipocyte cortical actin Mol Biol Cell 14, 3578–3591 Maffucci, T., Brancaccio, A., Piccolo, E., Stein, R C and Falasca, M (20 03) Insulin induces phosphatidylinositol-3-phosphate formation through TC10 activation EMBO J 22 , 4178–4189 Inoue,... receptor by a pathway independent of insulin receptor substrates Endocrinology 144, 3811–3 820 3 92 Tengholm, A and Meyer, T (20 02) A PI3-kinase signaling code for insulin- triggered insertion of glucose transporters into the plasma membrane Curr Biol 12, 1871–1876 393 Khan, A H and Pessin, J E (20 02) Insulin regulation of glucose uptake: a complex interplay of intracellular signaling pathways Diabetologia... tyrosine phosphorylation of caveolin-1 J Biol Chem 27 7, 30 153–30 158 361 Najjar, S (20 02) Regulation of insulin action by CEACAM1 Trends Endocrinol Metab 13, 24 0 24 5 REFERENCES 61 3 62 Myers, M G., Mendez, R., Shi, P., Pierce, J H., Rhoads, R and White, M F (1998) The COOH-terminal tyrosine phosphorylation sites on IRS-1 bind SHP -2 and negatively regulate insulin signaling J Biol Chem 27 3, 26 908 26 ... Siddle, K and O’Rahilly, S (20 02) Microarray analysis of insulin and IGF-1 receptor signalling reveals the selective up-regulation of the mitogen HB-EGF by IGF-1 J Biol Chem 27 7, 42 480– 42 487 2 Insulin- mediated Regulation of Glucose Metabolism Daniel Konrad, Assaf Rudich and Amira Klip 2. 1 Introduction Insulin was identified in the early 1 920 s as the major hypoglycaemic hormone, capable of restoring normal... 93–97  62 THE INSULIN RECEPTOR AND DOWNSTREAM SIGNALLING 378 Etienne-Manneville, S and Hall, A (20 02) Rho GTPases in cell biology Nature 420 , 629 –635 379 Houslay, M D and Siddle, K (1989) Molecular basis of insulin receptor function Br Med Bull 45, 26 4 28 4 380 Dalle, S., Ricketts, W., Imamura, T., Vollenweider, P and Olefsky, J M (20 01) Insulin and IGF-I receptors utilize different G-protein signaling... suggest that the actions of insulin in ‘nonclassical insulin targets’ are indirectly involved in the regulation of total body glucose metabolism It will be interesting to see whether in addition insulin regulates glucose metabolism in these sites In summary, insulin engages both ‘classical’ and ‘non-classical’ target organs in orchestrating the control of glucose metabolism (Table 2. 1) In its classical . Holdago-Madruga, M. and Wong, A. J. (20 01) Grb- 2- associated binder-1 is involved in insulin- induced egr-1 gene expression through its phosphatidylinositol 3  -kinase binding site. DNA Cell Biol 20 ,. (20 00) SOCS-3 is an insulin- induced negative regulator of insulin signaling. JBiolChem275, 15 985–15 991. 22 2. Ahmed, Z. and Pillay, T. S. (20 01) Functional effects of APS and SH2-B on insulin receptor. Distinct modes of interaction of SHC and insulin receptor substrate-1 with the insulin receptor NPEY region via non- SH2 domains. JBiolChem270, 23 25 8 23 26 2. 1 42. van der Geer, P., Wiley, S. and