Critical nodes in signalling pathways: insights into insulin action (original) (raw)

• Avruch, J. Insulin signal transduction through protein kinase cascades. Mol. Cell Biochem. 182, 31–48 (1998).
  Article CAS PubMed Google Scholar
• Ullrich, A. & Schlessinger, J. Signal transduction by receptors with tyrosine kinase activity. Cell 61, 203–212 (1990).
  CAS PubMed Google Scholar
• Elchebly, M. et al. Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science 283, 1544–1548 (1999).
  Article CAS PubMed Google Scholar
• Ueki, K., Kondo, T. & Kahn, C. R. Suppressor of cytokine signaling 1 (SOCS-1) and SOCS-3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms. Mol. Cell Biol. 24, 5434–5446 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Emanuelli, B. et al. SOCS-3 inhibits insulin signaling and is up-regulated in response to tumor necrosis factor-α in the adipose tissue of obese mice. J. Biol. Chem. 276, 47944–47949 (2001).
  Article CAS PubMed Google Scholar
• Friedman, J. E. et al. Reduced insulin receptor signaling in the obese spontaneously hypertensive Koletsky rat. Am. J. Physiol. 273, E1014–E1023 (1997).
  CAS PubMed Google Scholar
• Sun, X. J. et al. Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Nature 352, 73–77 (1991).
  Article CAS PubMed Google Scholar
• Sun, X. J. et al. Role of IRS-2 in insulin and cytokine signalling. Nature 377, 173–177 (1995).
  Article CAS PubMed Google Scholar
• Lavan, B. E., Lane, W. S. & Lienhard, G. E. The 60-kDa phosphotyrosine protein in insulin-treated adipocytes is a new member of the insulin receptor substrate family. J. Biol. Chem. 272, 11439–11443 (1997).
  Article CAS PubMed Google Scholar
• Fantin, V. R. et al. Characterization of insulin receptor substrate 4 in human embryonic kidney 293 cells. J. Biol. Chem. 273, 10726–10732 (1998).
  Article CAS PubMed Google Scholar
• Cai, D., Dhe-Paganon, S., Melendez, P. A., Lee, J. & Shoelson, S. E. Two new substrates in insulin signaling, IRS5/DOK4 and IRS6/DOK5. J. Biol. Chem. 278, 25323–25330 (2003).
  Article CAS PubMed Google Scholar
• Lehr, S. et al. Identification of major tyrosine phosphorylation sites in the human insulin receptor substrate Gab-1 by insulin receptor kinase in vitro. Biochemistry 39, 10898–10907 (2000).
  Article CAS PubMed Google Scholar
• Baumann, C. A. et al. CAP defines a second signalling pathway required for insulin-stimulated glucose transport. Nature 407, 202–207 (2000).
  Article CAS PubMed Google Scholar
• Gustafson, T. A., He, W., Craparo, A., Schaub, C. D. & O'Neill, T. J. Phosphotyrosine-dependent interaction of SHC and insulin receptor substrate 1 with the NPEY motif of the insulin receptor via a novel non-SH2 domain. Mol. Cell Biol. 15, 2500–2508 (1995).
  Article CAS PubMed PubMed Central Google Scholar
• Virkamaki, A., Ueki, K. & Kahn, C. R. Protein–protein interaction in insulin signaling and the molecular mechanisms of insulin resistance. J. Clin. Invest. 103, 931–943 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Myers, M. G. Jr et al. The COOH-terminal tyrosine phosphorylation sites on IRS-1 bind SHP-2 and negatively regulate insulin signaling. J. Biol. Chem. 273, 26908–26914 (1998).
  Article CAS PubMed Google Scholar
• Algenstaedt, P., Antonetti, D. A., Yaffe, M. B. & Kahn, C. R. Insulin receptor substrate proteins create a link between the tyrosine phosphorylation cascade and the Ca2+-ATPases in muscle and heart. J. Biol. Chem. 272, 23696–23702 (1997).
  Article CAS PubMed Google Scholar
• Fei, Z. L., D'Ambrosio, C., Li, S., Surmacz, E. & Baserga, R. Association of insulin receptor substrate 1 with simian virus 40 large T antigen. Mol. Cell Biol. 15, 4232–4239 (1995).
  Article CAS PubMed PubMed Central Google Scholar
• Zick, Y. Ser/Thr phosphorylation of IRS proteins: a molecular basis for insulin resistance. Sci. STKE 2005, PE4 (2005).
  Article PubMed Google Scholar
• Bouzakri, K. et al. 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 (2003).
  Article CAS PubMed Google Scholar
• Harrington, L. S. et al. The TSC1–2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J. Cell Biol. 166, 213–223 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Miller, B. S. et al. Activation of cJun NH2-terminal kinase/stress-activated protein kinase by insulin. Biochemistry 35, 8769–8775 (1996).
  Article CAS PubMed Google Scholar
• Cai, D. et al. Local and systemic insulin resistance resulting from hepatic activation of IKK-β and NF-κB. Nature Med. 11, 183–190 (2005).
  Article CAS PubMed Google Scholar
• Hirosumi, J. et al. A central role for JNK in obesity and insulin resistance. Nature 420, 333–336 (2002).
  Article CAS PubMed Google Scholar
• Aguirre, V., Uchida, T., Yenush, L., Davis, R. & White, M. F. The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307). J. Biol. Chem. 275, 9047–9054 (2000). An important paper that established the connection between Ser307 phosphorylation, JNK and insulin resistance.
  Article CAS PubMed Google Scholar
• Craparo, A., Freund, R. & Gustafson, T. A. 14-3-3 (ε) interacts with the insulin-like growth factor I receptor and insulin receptor substrate I in a phosphoserine-dependent manner. J. Biol. Chem. 272, 11663–11669 (1997).
  Article CAS PubMed Google Scholar
• Bard-Chapeau, E. A. et al. Deletion of Gab1 in the liver leads to enhanced glucose tolerance and improved hepatic insulin action. Nature Med. 11, 567–571 (2005).
  Article CAS PubMed Google Scholar
• Hirashima, Y. et al. Insulin down-regulates insulin receptor substrate-2 expression through the phosphatidylinositol 3-kinase/Akt pathway. J. Endocrinol. 179, 253–266 (2003).
  Article CAS PubMed Google Scholar
• Rui, L., Yuan, M., Frantz, D., Shoelson, S. & White, M. F. SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. J. Biol. Chem. 277, 42394–42398 (2002).
  Article CAS PubMed Google Scholar
• Shimomura, I. et al. Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice. Mol. Cell 6, 77–86 (2000).
  Article CAS PubMed Google Scholar
• Sesti, G. et al. Defects of the insulin receptor substrate (IRS) system in human metabolic disorders. FASEB J. 15, 2099–2111 (2001).
  Article CAS PubMed Google Scholar
• Araki, E. et al. Alternative pathway of insulin signaling in targeted disruption of the IRS-1 gene. Nature 372, 186–190 (1994).
  Article CAS PubMed Google Scholar
• Kubota, N. et al. Insulin receptor substrate 2 plays a crucial role in β cells and the hypothalamus. J. Clin. Invest. 114, 917–927 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Withers, D. J. et al. Disruption of IRS-2 causes type 2 diabetes in mice. Nature 391, 900–904 (1998).
  Article CAS PubMed Google Scholar
• Tseng, Y. H. et al. Prediction of preadipocyte differentiation by gene expression reveals role of insulin receptor substrates and necdin. Nature Cell Biol. 7, 601–611 (2005).
  Article CAS PubMed Google Scholar
• Miki, H. et al. Essential role of insulin receptor substrate 1 (IRS-1) and IRS-2 in adipocyte differentiation. Mol. Cell Biol. 21, 2521–2532 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Huang, C., Thirone, A. C., Huang, X. & Klip, A. Differential contribution of insulin receptor substrates 1 versus 2 to insulin signaling and glucose uptake in l6 myotubes. J. Biol. Chem. 280, 19426–19435 (2005).
  Article CAS PubMed Google Scholar
• Taniguchi, C. M., Ueki, K. & Kahn, R. Complementary roles of IRS-1 and IRS-2 in the hepatic regulation of metabolism. J. Clin. Invest. 115, 718–727 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Sun, X. J. et al. The IRS-2 gene on murine chromosome 8 encodes a unique signaling adapter for insulin and cytokine action. Mol. Endocrinol. 11, 251–262 (1997).
  Article CAS PubMed Google Scholar
• Miura, A. et al. Insulin substrates 1 and 2 are corequired for activation of atypical protein kinase C and Cbl-dependent phosphatidylinositol 3-kinase during insulin action in immortalized brown adipocytes. Biochemistry 43, 15503–15509 (2004).
  Article CAS PubMed Google Scholar
• Tsuruzoe, K., Emkey, R., Kriauciunas, K. M., Ueki, K. & Kahn, C. R. Insulin receptor substrate 3 (IRS-3) and IRS-4 impair IRS-1- and IRS-2-mediated signaling. Mol. Cell Biol. 21, 26–38 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Inoue, G., Cheatham, B., Emkey, R. & Kahn, C. R. Dynamics of insulin signaling in 3T3-L1 adipocytes. Differential compartmentalization and trafficking of insulin receptor substrate (IRS)-1 and IRS-2. J. Biol. Chem. 273, 11548–11555 (1998).
  Article CAS PubMed Google Scholar
• Ogihara, T. et al. Insulin receptor substrate (IRS)-2 is dephosphorylated more rapidly than IRS-1 via its association with phosphatidylinositol 3-kinase in skeletal muscle cells. J. Biol. Chem. 272, 12868–12873 (1997).
  Article CAS PubMed Google Scholar
• Sawka-Verhelle, D., Tartare-Deckert, S., White, M. F. & Van Obberghen, E. Insulin receptor substrate-2 binds to the insulin receptor through its phosphotyrosine-binding domain and through a newly identified domain comprising amino acids 591–786. J. Biol. Chem. 271, 5980–5983 (1996).
  Article CAS PubMed Google Scholar
• Myers, M. G. Jr et al. IRS-1 activates phosphatidylinositol 3′-kinase by associating with src homology 2 domains of p85. Proc. Natl Acad. Sci. USA 89, 10350–10354 (1992).
  Article CAS PubMed PubMed Central Google Scholar
• Cheatham, B. et al. Phosphatidylinositol 3-kinase activation is required for insulin stimulation of pp70 S6 kinase, DNA synthesis, and glucose transporter translocation. Mol. Cell Biol. 14, 4902–4911 (1994).
  CAS PubMed PubMed Central Google Scholar
• Alessi, D. R. et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Bα. Curr. Biol. 7, 261–269 (1997). Describes the discovery of PDK1.
  Article CAS PubMed Google Scholar
• Le Good, J. A. et al. Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1. Science 281, 2042–2045 (1998).
  Article CAS PubMed Google Scholar
• Sarbassov, D. D., Guertin, D. A., Ali, S. M. & Sabatini, D. M. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307, 1098–1101 (2005).
  Article CAS PubMed Google Scholar
• Maehama, T. & Dixon, J. E. PTEN: a tumour suppressor that functions as a phospholipid phosphatase. Trends Cell Biol. 9, 125–128 (1999).
  Article CAS PubMed Google Scholar
• Wijesekara, N. et al. Muscle-specific Pten deletion protects against insulin resistance and diabetes. Mol. Cell Biol. 25, 1135–1145 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Tang, X., Powelka, A. M., Soriano, N. A., Czech, M. P. & Guilherme, A. PTEN, but not SHIP2, suppresses insulin signaling through the phosphatidylinositol 3-kinase/Akt pathway in 3T3-L1 adipocytes. J. Biol. Chem. 280, 22523–22529 (2005).
  Article CAS PubMed Google Scholar
• Sleeman, M. W. et al. Absence of the lipid phosphatase SHIP2 confers resistance to dietary obesity. Nature Med. 11, 199–205 (2005).
  Article CAS PubMed Google Scholar
• Shepherd, P. R., Withers, D. J. & Siddle, K. Phosphoinositide 3-kinase: the key switch mechanism in insulin signalling. Biochem. J. 333, 471–490 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Yu, J. et al. Regulation of the p85/p110 phosphatidylinositol 3′-kinase: stabilization and inhibition of the p110α catalytic subunit by the p85 regulatory subunit. Mol. Cell Biol. 18, 1379–1387 (1998). Helped to define the molecular and functional relationships between the regulatory and catalytic subunits of PI3K.
  Article CAS PubMed PubMed Central Google Scholar
• Asano, T. et al. p110β is up-regulated during differentiation of 3T3-L1 cells and contributes to the highly insulin-responsive glucose transport activity. J. Biol. Chem. 275, 17671–17676 (2000).
  Article CAS PubMed Google Scholar
• Tanti, J. F., Gremeaux, T., Van Obberghen, E. & Le Marchand-Brustel, Y. Insulin receptor substrate 1 is phosphorylated by the serine kinase activity of phosphatidylinositol 3-kinase. Biochem. J. 304, 17–21 (1994).
  Article CAS PubMed PubMed Central Google Scholar
• Tanti, J. F., Gremeaux, T., van Obberghen, E. & Le Marchand-Brustel, Y. Serine/threonine phosphorylation of insulin receptor substrate 1 modulates insulin receptor signaling. J. Biol. Chem. 269, 6051–6057 (1994).
  Article CAS PubMed Google Scholar
• Antonetti, D. A., Algenstaedt, P. & Kahn, C. R. Insulin receptor substrate 1 binds two novel splice variants of the regulatory subunit of phosphatidylinositol 3-kinase in muscle and brain. Mol. Cell Biol. 16, 2195–2203 (1996).
  Article CAS PubMed PubMed Central Google Scholar
• Ueki, K. et al. Increased insulin sensitivity in mice lacking p85β subunit of phosphoinositide 3-kinase. Proc. Natl Acad. Sci. USA 99, 419–424 (2002).
  Article CAS PubMed Google Scholar
• Terauchi, Y. et al. Increased insulin sensitivity and hypoglycaemia in mice lacking the p85 α subunit of phosphoinositide 3-kinase. Nature Genet. 21, 230–235 (1999). The first description of the paradoxical negative regulation of insulin signalling by the regulatory subunit p85α.
  Article CAS PubMed Google Scholar
• Chen, D. et al. p50α/p55α phosphoinositide 3-kinase knockout mice exhibit enhanced insulin sensitivity. Mol. Cell Biol. 24, 320–329 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Fruman, D. A. et al. Hypoglycaemia, liver necrosis and perinatal death in mice lacking all isoforms of phosphoinositide 3-kinase p85 α. Nature Genet. 26, 379–382 (2000).
  Article CAS PubMed Google Scholar
• Mauvais-Jarvis, F. et al. Reduced expression of the murine p85α subunit of phosphoinositide 3-kinase improves insulin signaling and ameliorates diabetes. J. Clin. Invest. 109, 141–149 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Barbour, L. A. et al. Human placental growth hormone increases expression of the p85 regulatory unit of phosphatidylinositol 3-kinase and triggers severe insulin resistance in skeletal muscle. Endocrinology 145, 1144–1150 (2004). Shows that the physiologic upregulation of p85α in vivo induces insulin resistance.
  Article CAS PubMed Google Scholar
• Bandyopadhyay, G. K., Yu, J. G., Ofrecio, J. & Olefsky, J. M. Increased p85/55/50 expression and decreased phosphatidylinositol 3-kinase activity in insulin-resistant human skeletal muscle. Diabetes 54, 2351–2359 (2005).
  Article CAS PubMed Google Scholar
• Ueki, K., Algenstaedt, P., Mauvais-Jarvis, F. & Kahn, C. R. Positive and negative regulation of phosphoinositide 3-kinase-dependent signaling pathways by three different gene products of the p85α regulatory subunit. Mol. Cell Biol. 20, 8035–8046 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Luo, J., Field, S. J., Lee, J. Y., Engelman, J. A. & Cantley, L. C. The p85 regulatory subunit of phosphoinositide 3-kinase down-regulates IRS-1 signaling via the formation of a sequestration complex. J. Cell Biol. 170, 455–464 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Ueki, K. et al. Positive and negative roles of p85 α and p85 β regulatory subunits of phosphoinositide 3-kinase in insulin signaling. J. Biol. Chem. 278, 48453–48466 (2003). The first published connection between the p85α regulatory subunit and JNK activation.
  Article CAS PubMed Google Scholar
• Carpenter, C. L. & Cantley, L. C. Phosphoinositide kinases. Curr. Opin. Cell Biol. 8, 153–158 (1996).
  Article CAS PubMed Google Scholar
• Fang, D. & Liu, Y. C. Proteolysis-independent regulation of PI3K by Cbl-b-mediated ubiquitination in T cells. Nature Immunol. 2, 870–875 (2001).
  Article CAS Google Scholar
• Zheng, Y., Bagrodia, S. & Cerione, R. A. Activation of phosphoinositide 3-kinase activity by Cdc42Hs binding to p85. J. Biol. Chem. 269, 18727–18730 (1994).
  Article CAS PubMed Google Scholar
• Cross, D. A., Alessi, D. R., Cohen, P., Andjelkovich, M. & Hemmings, B. A. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378, 785–789 (1995).
  Article CAS PubMed Google Scholar
• Frame, S. & Cohen, P. GSK3 takes centre stage more than 20 years after its discovery. Biochem. J. 359, 1–16 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Sano, H. et al. Insulin-stimulated phosphorylation of a Rab GTPase-activating protein regulates GLUT4 translocation. J. Biol. Chem. 278, 14599–14602 (2003).
  Article CAS PubMed Google Scholar
• Harris, T. E. & Lawrence, J. C. Jr. TOR signaling. Sci. STKE 2003, RE15 (2003).
  Article PubMed Google Scholar
• Tran, H., Brunet, A., Griffith, E. C. & Greenberg, M. E. The many forks in FOXO's road. Sci. STKE 2003, RE5 (2003).
  Article PubMed Google Scholar
• Puigserver, P. et al. Insulin-regulated hepatic gluconeogenesis through FOXO1–PGC-1α interaction. Nature 423, 550–555 (2003).
  Article CAS PubMed Google Scholar
• Nakae, J. et al. The forkhead transcription factor Foxo1 regulates adipocyte differentiation. Dev. Cell 4, 119–129 (2003).
  Article CAS PubMed Google Scholar
• Wolfrum, C., Asilmaz, E., Luca, E., Friedman, J. M. & Stoffel, M. Foxa2 regulates lipid metabolism and ketogenesis in the liver during fasting and in diabetes. Nature 432, 1027–1032 (2004).
  Article CAS PubMed Google Scholar
• Brazil, D. P., Yang, Z. Z. & Hemmings, B. A. Advances in protein kinase B signalling: AKTion on multiple fronts. Trends Biochem. Sci. 29, 233–242 (2004).
  Article CAS PubMed Google Scholar
• Gao, T., Furnari, F. & Newton, A. C. PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth. Mol. Cell 18, 13–24 (2005).
  Article CAS PubMed Google Scholar
• Du, K., Herzig, S., Kulkarni, R. N. & Montminy, M. TRB3: a tribbles homolog that inhibits Akt/PKB activation by insulin in liver. Science 300, 1574–1577 (2003).
  Article CAS PubMed Google Scholar
• Koo, S. H. et al. PGC-1 promotes insulin resistance in liver through PPAR-α-dependent induction of TRB-3. Nature Med. 10, 530–534 (2004).
  Article CAS PubMed Google Scholar
• Chen, W. S. et al. Growth retardation and increased apoptosis in mice with homozygous disruption of the Akt1 gene. Genes Dev. 15, 2203–2208 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Cho, H., Thorvaldsen, J. L., Chu, Q., Feng, F. & Birnbaum, M. J. Akt1/PKBα is required for normal growth but dispensable for maintenance of glucose homeostasis in mice. J. Biol. Chem. 276, 38349–38352 (2001).
  Article CAS PubMed Google Scholar
• Cho, H. et al. Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKBβ). Science 292, 1728–1731 (2001).
  Article CAS PubMed Google Scholar
• George, S. et al. A family with severe insulin resistance and diabetes due to a mutation in AKT2. Science 304, 1325–1328 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Tschopp, O. et al. Essential role of protein kinase B γ (PKB γ/Akt3) in postnatal brain development but not in glucose homeostasis. Development 132, 2943–2954 (2005).
  Article CAS PubMed Google Scholar
• Chan, T. O., Rittenhouse, S. E. & Tsichlis, P. N. AKT/PKB and other D3 phosphoinositide-regulated kinases: kinase activation by phosphoinositide-dependent phosphorylation. Annu. Rev. Biochem. 68, 965–1014 (1999).
  Article CAS PubMed Google Scholar
• Bae, S. S., Cho, H., Mu, J. & Birnbaum, M. J. Isoform-specific regulation of insulin-dependent glucose uptake by Akt/protein kinase B. J. Biol. Chem. 278, 49530–49536 (2003).
  Article CAS PubMed Google Scholar
• Jiang, Z. Y. et al. Insulin signaling through Akt/protein kinase B analyzed by small interfering RNA-mediated gene silencing. Proc. Natl Acad. Sci. USA 100, 7569–7574 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Calera, M. R. et al. Insulin increases the association of Akt-2 with Glut4-containing vesicles. J. Biol. Chem. 273, 7201–7204 (1998).
  Article CAS PubMed Google Scholar
• Yamada, E. et al. Akt2 phosphorylates Synip to regulate docking and fusion of GLUT4-containing vesicles. J. Cell Biol. 168, 921–928 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Masure, S. et al. Molecular cloning, expression and characterization of the human serine/threonine kinase Akt-3. Eur. J. Biochem. 265, 353–360 (1999).
  Article CAS PubMed Google Scholar
• Standaert, M. L., Bandyopadhyay, G., Kanoh, Y., Sajan, M. P. & Farese, R. V. Insulin and PIP3 activate PKC-ζ by mechanisms that are both dependent and independent of phosphorylation of activation loop (T410) and autophosphorylation (T560) sites. Biochemistry 40, 249–255 (2001).
  Article CAS PubMed Google Scholar
• Farese, R. V. Function and dysfunction of aPKC isoforms for glucose transport in insulin-sensitive and insulin-resistant states. Am. J. Physiol. Endocrinol. Metab. 283, E1–E11 (2002).
  Article CAS PubMed Google Scholar
• Farese, R. V., Sajan, M. P. & Standaert, M. L. Atypical protein kinase C in insulin action and insulin resistance. Biochem. Soc. Trans. 33, 350–353 (2005).
  Article CAS PubMed Google Scholar
• Pouyssegur, J., Volmat, V. & Lenormand, P. Fidelity and spatio-temporal control in MAP kinase (ERKs) signalling. Biochem. Pharmacol. 64, 755–763 (2002).
  Article CAS PubMed Google Scholar
• Pages, G. et al. Defective thymocyte maturation in p44 MAP kinase (Erk 1) knockout mice. Science 286, 1374–1377 (1999).
  Article CAS PubMed Google Scholar
• Bost, F. et al. The extracellular signal-regulated kinase isoform ERK1 is specifically required for in vitro and in vivo adipogenesis. Diabetes 54, 402–411 (2005).
  Article CAS PubMed Google Scholar
• Hancock, J. F. & Parton, R. G. Ras plasma membrane signalling platforms. Biochem. J. 389, 1–11 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Rodriguez-Viciana, P. et al. Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 370, 527–532 (1994).
  Article CAS PubMed Google Scholar
• Wellbrock, C., Karasarides, M. & Marais, R. The RAF proteins take centre stage. Nature Rev. Mol. Cell Biol. 5, 875–885 (2004).
  Article CAS Google Scholar
• Matos, P. et al. Small GTPase Rac1: structure, localization, and expression of the human gene. Biochem. Biophys. Res. Commun. 277, 741–751 (2000).
  Article CAS PubMed Google Scholar
• Marks, P. W. & Kwiatkowski, D. J. Genomic organization and chromosomal location of murine Cdc42. Genomics 38, 13–18 (1996).
  Article CAS PubMed Google Scholar
• Marcusohn, J., Isakoff, S. J., Rose, E., Symons, M. & Skolnik, E. Y. The GTP-binding protein Rac does not couple PI 3-kinase to insulin-stimulated glucose transport in adipocytes. Curr. Biol. 5, 1296–1302 (1995).
  Article CAS PubMed Google Scholar
• Usui, I., Imamura, T., Huang, J., Satoh, H. & Olefsky, J. M. Cdc42 is a Rho GTPase family member that can mediate insulin signaling to glucose transport in 3T3-L1 adipocytes. J. Biol. Chem. 278, 13765–13774 (2003).
  Article CAS PubMed Google Scholar
• Ip, Y. T. & Davis, R. J. Signal transduction by the c-Jun N-terminal kinase (JNK) — from inflammation to development. Curr. Opin. Cell Biol. 10, 205–219 (1998).
  Article CAS PubMed Google Scholar
• Zarubin, T. & Han, J. Activation and signaling of the p38 MAP kinase pathway. Cell Res. 15, 11–18 (2005).
  Article CAS PubMed Google Scholar
• Furtado, L. M., Somwar, R., Sweeney, G., Niu, W. & Klip, A. Activation of the glucose transporter GLUT4 by insulin. Biochem. Cell Biol. 80, 569–578 (2002).
  Article CAS PubMed Google Scholar
• Carlson, C. J., Koterski, S., Sciotti, R. J., Poccard, G. B. & Rondinone, C. M. Enhanced basal activation of mitogen-activated protein kinases in adipocytes from type 2 diabetes: potential role of p38 in the downregulation of GLUT4 expression. Diabetes 52, 634–641 (2003).
  Article CAS PubMed Google Scholar
• Chiang, S. H. et al. TCGAP, a multidomain Rho GTPase-activating protein involved in insulin-stimulated glucose transport. EMBO J. 22, 2679–2691 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Thien, C. B. & Langdon, W. Y. Cbl: many adaptations to regulate protein tyrosine kinases. Nature Rev. Mol. Cell Biol. 2, 294–307 (2001).
  Article CAS Google Scholar
• Molero, J. C. et al. c-Cbl-deficient mice have reduced adiposity, higher energy expenditure, and improved peripheral insulin action. J. Clin. Invest. 114, 1326–1333 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Zhou, Q. L. et al. Analysis of insulin signalling by RNAi-based gene silencing. Biochem. Soc. Trans. 32, 817–821 (2004).
  Article CAS PubMed Google Scholar
• Stegmeier, F., Hu, G., Rickles, R. J., Hannon, G. J. & Elledge, S. J. A lentiviral microRNA-based system for single-copy polymerase II-regulated RNA interference in mammalian cells. Proc. Natl Acad. Sci. USA 102, 13212–13217 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Shinagawa, T. & Ishii, S. Generation of Ski-knockdown mice by expressing a long double-strand RNA from an RNA polymerase II promoter. Genes Dev. 17, 1340–1345 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Ding, S. et al. Efficient transposition of the piggyBac (PB) transposon in mammalian cells and mice. Cell 122, 473–483 (2005).
  Article CAS PubMed Google Scholar
• Becker, A. B. & Roth, R. A. Insulin receptor structure and function in normal and pathological conditions. Annu. Rev. Med. 41, 99–115 (1990).
  Article CAS PubMed Google Scholar
• Goren, H. J., White, M. F. & Kahn, C. R. Separate domains of the insulin receptor contain sites of autophosphorylation and tyrosine kinase activity. Biochemistry 26, 2374–2382 (1987).
  Article CAS PubMed Google Scholar
• Sesti, G. et al. Tissue-specific expression of two alternatively spliced isoforms of the human insulin receptor protein. Acta Diabetol. 31, 59–65 (1994).
  Article CAS PubMed Google Scholar
• Yamaguchi, Y. et al. Functional properties of two naturally occurring isoforms of the human insulin receptor in Chinese hamster ovary cells. Endocrinology 129, 2058–2066 (1991).
  Article CAS PubMed Google Scholar
• Leibiger, B. et al. Selective insulin signaling through A and B insulin receptors regulates transcription of insulin and glucokinase genes in pancreatic β cells. Mol. Cell 7, 559–570 (2001).
  Article CAS PubMed Google Scholar
• Bhalla, U. S. & Iyengar, R. Emergent properties of networks of biological signaling pathways. Science 283, 381–387 (1999).
  Article CAS PubMed Google Scholar