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Insulin Resistance and Cancer pp 53–76Cite as

Insulin/IGF-1 Signaling Nodes and their Role in Carcinogenesis

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Part of the book series: Energy Balance and Cancer ((EBAC,volume 1))

Abstract

The dominant hormone regulating metabolic homeostasis and the switch between the anabolic and catabolic states is insulin. At the cellular level, the action of insulin and the closely related insulin-like growth factors (IGF)-1 and -2, are mediated through a complex network of diverging and converging events (reviewed in [1]). The insulin and IGF-1 receptors (IR and IGF-1R) are members of the family of receptor tyrosine kinases. Following hormone binding, these receptors undergo autophosphorylation, which activates the kinase toward other substrates termed the insulin receptor substrate (IRS) proteins. In contrast to most other tyrosine kinase receptors, it is the phosphorylated IRS proteins, rather than the receptors themselves, that link the action of these hormones to two main signaling pathways: the phosphatidylinositol 3-kinase (PI3K)-Akt pathway, which is responsible for most of the metabolic actions of insulin, and the Ras-MAP kinase pathway, which regulates expression of some genes and cooperates with the PI3K pathway to control cell growth and differentiation (reviewed in [2]) (Fig. 2.1).

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References

  1. Taniguchi CM, Emanuelli B, Kahn CR (2006) Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol 7:85–96

    Article  CAS  PubMed  Google Scholar 

  2. Avruch J (1998) Insulin signal transduction through protein kinase cascades. Mol Cell Biochem 182:31–48

    Article  CAS  PubMed  Google Scholar 

  3. Barone BB, Yeh HC, Snyder CF, Peairs KS, Stein KB et al (2008) Long-term all-cause mortality in cancer patients with preexisting diabetes mellitus: a systematic review and meta-analysis. JAMA 300:2754–2764

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Whitlock G, Lewington S, Sherliker P, Clarke R, Emberson J et al (2009) Body-mass index and cause-specific mortality in 900,000 adults: collaborative analyses of 57 prospective studies. Lancet 373:1083–1096

    Article  PubMed  Google Scholar 

  5. Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M (2008) Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 371:569–578

    Article  PubMed  Google Scholar 

  6. Vairaktaris E, Spyridonidou S, Goutzanis L, Vylliotis A, Lazaris A et al (2007) Diabetes and oral oncogenesis. Anticancer Res 27:4185–4193

    CAS  PubMed  Google Scholar 

  7. Wunderlich FT, Luedde T, Singer S, Schmidt-Supprian M, Baumgartl J et al (2008) Hepatic NF-kappa B essential modulator deficiency prevents obesity-induced insulin resistance but synergizes with high-fat feeding in tumorigenesis. Proc Natl Acad Sci USA 105:1297–1302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Zhang B, Roth RA (1992) The insulin receptor-related receptor. Tissue expression, ligand binding specificity, and signaling capabilities. J Biol Chem 267:18320–18328

    Article  CAS  PubMed  Google Scholar 

  9. Becker AB, Roth RA (1990) Insulin receptor structure and function in normal and pathological conditions. Annu Rev Med 41:99–115

    Article  CAS  PubMed  Google Scholar 

  10. Hedo JA, Kahn CR, Hayashi M, Yamada KM, Kasuga M (1983) Biosynthesis and glycosylation of the insulin receptor. Evidence for a single polypeptide precursor of the two major subunits. J Biol Chem 258:10020–10026

    Article  CAS  PubMed  Google Scholar 

  11. Baron V, Kaliman P, Gautier N, Van Obberghen E (1992) The insulin receptor activation process involves localized conformational changes. J Biol Chem 267:23290–23294

    Article  CAS  PubMed  Google Scholar 

  12. Ablooglu AJ, Kohanski RA (2001) Activation of the insulin receptor’s kinase domain changes the rate-determining step of substrate phosphorylation. Biochemistry 40:504–513

    Article  CAS  PubMed  Google Scholar 

  13. Goren HJ, White MF, Kahn CR (1987) Separate domains of the insulin receptor contain sites of autophosphorylation and tyrosine kinase activity. Biochemistry 26:2374–2382

    Article  CAS  PubMed  Google Scholar 

  14. Desbois-Mouthon C, Sert-Langeron C, Magre J, Oreal E, Blivet MJ et al (1996) Deletion of Asn281 in the alpha-subunit of the human insulin receptor causes constitutive activation of the receptor and insulin desensitization. J Clin Endocrinol Metab 81:719–727

    CAS  PubMed  Google Scholar 

  15. Elchebly M, Payette P, Michaliszyn E, Cromlish W, Collins S et al (1999) Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene. Science 283:1544–1548

    Article  CAS  PubMed  Google Scholar 

  16. Klaman LD, Boss O, Peroni OD, Kim JK, Martino JL et al (2000) Increased energy expenditure, decreased adiposity, and tissue-specific insulin sensitivity in protein-tyrosine phosphatase 1B-deficient mice. Mol Cell Biol 20:5479–5489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zinker BA, Rondinone CM, Trevillyan JM, Gum RJ, Clampit JE et al (2002) PTP1B antisense oligonucleotide lowers PTP1B protein, normalizes blood glucose, and improves insulin sensitivity in diabetic mice. Proc Natl Acad Sci USA 99:11357–11362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Rondinone CM, Trevillyan JM, Clampit J, Gum RJ, Berg C et al (2002) Protein tyrosine phosphatase 1B reduction regulates adiposity and expression of genes involved in lipogenesis. Diabetes 51:2405–2411

    Article  CAS  PubMed  Google Scholar 

  19. Gum RJ, Gaede LL, Koterski SL, Heindel M, Clampit JE et al (2003) Reduction of protein tyrosine phosphatase 1B increases insulin-dependent signaling in ob/ob mice. Diabetes 52:21–28

    Article  CAS  PubMed  Google Scholar 

  20. Ueki K, Kondo T, Tseng YH, Kahn CR (2004) Central role of suppressors of cytokine signaling proteins in hepatic steatosis, insulin resistance, and the metabolic syndrome in the mouse. Proc Natl Acad Sci USA 101:10422–10427

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Ueki K, Kondo T, Kahn CR (2004) 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Emanuelli B, Peraldi P, Filloux C, Sawka-Verhelle D, Hilton D et al (2000) SOCS-3 is an insulin-induced negative regulator of insulin signaling. J Biol Chem 275:15958–15991

    Article  Google Scholar 

  23. Emanuelli B, Peraldi P, Filloux C, Chavey C, Freidinger K et al (2001) SOCS-3 inhibits insulin signaling and is up-regulated in response to tumor necrosis factor-alpha in the adipose tissue of obese mice. J Biol Chem 276:47944–47949

    Article  CAS  PubMed  Google Scholar 

  24. Wick KR, Werner ED, Langlais P, Ramos FJ, Dong LQ et al (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. J Biol Chem 278:8460–8467

    Article  CAS  PubMed  Google Scholar 

  25. Dong H, Maddux BA, Altomonte J, Meseck M, Accili D et al (2005) Increased hepatic levels of the insulin receptor inhibitor, PC-1/NPP1, induce insulin resistance and glucose intolerance. Diabetes 54:367–372

    Article  CAS  PubMed  Google Scholar 

  26. Sutherland KD, Lindeman GJ, Visvader JE (2007) Knocking off SOCS genes in the mammary gland. Cell Cycle 6:799–803

    Article  CAS  PubMed  Google Scholar 

  27. McClain DA (1992) Mechanism and role of insulin receptor endocytosis. Am J Med Sci 304:192–201

    Article  CAS  PubMed  Google Scholar 

  28. Friedman JE, Ishizuka T, Liu S, Farrell CJ, Bedol D et al (1997) Reduced insulin receptor signaling in the obese spontaneously hypertensive Koletsky rat. Am J Physiol 273:E1014–E1023

    CAS  PubMed  Google Scholar 

  29. Mathieu MC, Clark GM, Allred DC, Goldfine ID, Vigneri R (1997) Insulin receptor expression and clinical outcome in node-negative breast cancer. Proc Assoc Am Physicians 109:565–571

    CAS  PubMed  Google Scholar 

  30. Sesti G, Tullio AN, D’Alfonso R, Napolitano ML, Marini MA et al (1994) Tissue-specific expression of two alternatively spliced isoforms of the human insulin receptor protein. Acta Diabetol 31:59–65

    Article  CAS  PubMed  Google Scholar 

  31. Pashmforoush M, Yoshimasa Y, Steiner DF (1994) Exon 11 enhances insulin binding affinity and tyrosine kinase activity of the human insulin proreceptor. J Biol Chem 269:32639–32648

    Article  CAS  PubMed  Google Scholar 

  32. Vogt B, Carrascosa JM, Ermel B, Ullrich A, Haring HU (1991) The two isotypes of the human insulin receptor (HIR-A and HIR-B) follow different internalization kinetics. Biochem Biophys Res Commun 177:1013–1018

    Article  CAS  PubMed  Google Scholar 

  33. Kosaki A, Pillay TS, Xu L, Webster NJ (1995) The B isoform of the insulin receptor signals more efficiently than the A isoform in HepG2 cells. J Biol Chem 270:20816–20823

    Article  CAS  PubMed  Google Scholar 

  34. Frasca F, Pandini G, Scalia P, Sciacca L, Mineo R et al (1999) Insulin receptor isoform A, a newly recognized, high-affinity insulin-like growth factor II receptor in fetal and cancer cells. Mol Cell Biol 19:3278–3288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Yamaguchi Y, Flier JS, Yokota A, Benecke H, Backer JM et al (1991) Functional properties of two naturally occurring isoforms of the human insulin receptor in Chinese hamster ovary cells. Endocrinology 129:2058–2066

    Article  CAS  PubMed  Google Scholar 

  36. Vella V, Pandini G, Sciacca L, Mineo R, Vigneri R et al (2002) A novel autocrine loop involving IGF-II and the insulin receptor isoform-A stimulates growth of thyroid cancer. J Clin Endocrinol Metab 87:245–254

    Article  CAS  PubMed  Google Scholar 

  37. Leibiger B, Leibiger IB, Moede T, Kemper S, Kulkarni RN et al (2001) Selective insulin signaling through A and B insulin receptors regulates transcription of insulin and glucokinase genes in pancreatic beta cells. Mol Cell 7:559–570

    Article  CAS  PubMed  Google Scholar 

  38. Ohlsson C, Kley N, Werner H, LeRoith D (1998) p53 regulates insulin-like growth factor-I (IGF-I) receptor expression and IGF-I-induced tyrosine phosphorylation in an osteosarcoma cell line: interaction between p53 and Sp1. Endocrinology 139:1101–1107

    Article  CAS  PubMed  Google Scholar 

  39. Girnita L, Girnita A, Brodin B, Xie Y, Nilsson G et al (2000) Increased expression of insulin-like growth factor I receptor in malignant cells expressing aberrant p53: functional impact. Cancer Res 60:5278–5283

    CAS  PubMed  Google Scholar 

  40. Frasca F, Pandini G, Sciacca L, Pezzino V, Squatrito S et al (2008) The role of insulin receptors and IGF-I receptors in cancer and other diseases. Arch Physiol Biochem 114:23–37

    Article  CAS  PubMed  Google Scholar 

  41. Sun XJ, Rothenberg P, Kahn CR, Backer JM, Araki E et al (1991) Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Nature 352:73–77

    Article  CAS  PubMed  Google Scholar 

  42. Sun XJ, Wang LM, Zhang Y, Yenush L, Myers MG Jr et al (1995) Role of IRS-2 in insulin and cytokine signalling. Nature 377:173–177

    Article  CAS  PubMed  Google Scholar 

  43. Lavan BE, Lane WS, Lienhard GE (1997) 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

    Article  CAS  PubMed  Google Scholar 

  44. Fantin VR, Sparling JD, Slot JW, Keller SR, Lienhard GE et al (1998) Characterization of insulin receptor substrate 4 in human embryonic kidney 293 cells. J Biol Chem 273:10726–10732

    Article  CAS  PubMed  Google Scholar 

  45. Cai D, Dhe-Paganon S, Melendez PA, Lee J, Shoelson SE (2003) Two new substrates in insulin signaling, IRS5/DOK4 and IRS6/DOK5. J Biol Chem 278:25323–25330

    Article  CAS  PubMed  Google Scholar 

  46. Lehr S, Kotzka J, Herkner A, Sikmann A, Meyer HE et al (2000) Identification of major tyrosine phosphorylation sites in the human insulin receptor substrate Gab-1 by insulin receptor kinase in vitro. Biochemistry 39:10898–10907

    Article  CAS  PubMed  Google Scholar 

  47. Wick MJ, Dong LQ, Hu D, Langlais P, Liu F (2001) Insulin receptor-mediated p62dok tyrosine phosphorylation at residues 362 and 398 plays distinct roles for binding GTPase-activating protein and Nck and is essential for inhibiting insulin-stimulated activation of Ras and Akt. J Biol Chem 276:42843–42850

    Article  CAS  PubMed  Google Scholar 

  48. Baumann CA, Ribon V, Kanzaki M, Thurmond DC, Mora S et al (2000) CAP defines a second signalling pathway required for insulin-stimulated glucose transport. Nature 407:202–207

    Article  CAS  PubMed  Google Scholar 

  49. Gustafson TA, He W, Craparo A, Schaub CD, O’Neill TJ (1995) 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Björnholm M, He AR, Attersand A, Lake S, Liu SC et al (2002) Absence of functional insulin receptor substrate-3 (IRS-3) gene in humans. Diabetologia 45:1697–702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Virkamaki A, Ueki K, Kahn CR (1999) Protein-protein interaction in insulin signaling and the molecular mechanisms of insulin resistance. J Clin Invest 103:931–943

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Skolnik EY, Lee CH, Batzer A, Vicentini LM, Zhou M et al (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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Myers MG Jr, Mendez R, Shi P, Pierce JH, Rhoads R et al (1998) The COOH-terminal tyrosine phosphorylation sites on IRS-1 bind SHP-2 and negatively regulate insulin signaling. J Biol Chem 273:26908–26914

    Article  CAS  PubMed  Google Scholar 

  54. Sun XJ, Pons S, Asano T, Myers MG Jr, Glasheen E et al (1996) The Fyn tyrosine kinase binds Irs-1 and forms a distinct signaling complex during insulin stimulation. J Biol Chem 271:10583–10587

    Article  CAS  PubMed  Google Scholar 

  55. Algenstaedt P, Antonetti DA, Yaffe MB, Kahn CR (1997) 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

    Article  CAS  PubMed  Google Scholar 

  56. Fei ZL, D’Ambrosio C, Li S, Surmacz E, Baserga R (1995) Association of insulin receptor substrate 1 with simian virus 40 large T antigen. Mol Cell Biol 15:4232–4239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Zick Y (2005) Ser/Thr phosphorylation of IRS proteins: a molecular basis for insulin resistance. Sci STKE 2005(268):pe4

    Article  PubMed  Google Scholar 

  58. Li J, DeFea K, Roth RA (1999) Modulation of insulin receptor substrate-1 tyrosine phosphorylation by an Akt/phosphatidylinositol 3-kinase pathway. J Biol Chem 274:9351–9356

    Article  CAS  PubMed  Google Scholar 

  59. Bard-Chapeau EA, Hevener AL, Long S, Zhang EE, Olefsky JM et al (2005) Deletion of Gab1 in the liver leads to enhanced glucose tolerance and improved hepatic insulin action. Nat Med 11:567–571

    Article  CAS  PubMed  Google Scholar 

  60. Harrington LS, Findlay GM, Gray A, Tolkacheva T, Wigfield S et al (2004) The TSC1-2 tumor suppressor controls insulin-PI3K signaling via regulation of IRS proteins. J Cell Biol 166:213–223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Aguirre V, Uchida T, Yenush L, Davis R, White MF (2000) 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

    Article  CAS  PubMed  Google Scholar 

  62. Hirosumi J, Tuncman G, Chang L, Gorgun CZ, Uysal KT et al (2002) A central role for JNK in obesity and insulin resistance. Nature 420:333–336

    Article  CAS  PubMed  Google Scholar 

  63. Werner ED, Lee J, Hansen L, Yuan M, Shoelson SE (2004) Insulin resistance due to phosphorylation of insulin receptor substrate-1 at serine 302. J Biol Chem 279:35298–35305

    Article  CAS  PubMed  Google Scholar 

  64. Craparo A, Freund R, Gustafson TA (1997) 14-3-3 (epsilon) 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

    Article  CAS  PubMed  Google Scholar 

  65. Tirosh A, Potashnik R, Bashan N, Rudich A (1999) Oxidative stress disrupts insulin-induced cellular redistribution of insulin receptor substrate-1 and phosphatidylinositol 3-kinase in 3T3-L1 adipocytes. A putative cellular mechanism for impaired protein kinase B activation and GLUT4 translocation. J Biol Chem 274:10595–10602

    Article  CAS  PubMed  Google Scholar 

  66. Pederson TM, Kramer DL, Rondinone CM (2001) Serine/threonine phosphorylation of IRS-1 triggers its degradation: possible regulation by tyrosine phosphorylation. Diabetes 50:24–31

    Article  CAS  PubMed  Google Scholar 

  67. Giraud J, Leshan R, Lee YH, White MF (2004) Nutrient-dependent and insulin-stimulated phosphorylation of insulin receptor substrate-1 on serine 302 correlates with increased insulin signaling. J Biol Chem 279:3447–3454

    Article  CAS  PubMed  Google Scholar 

  68. Furukawa N, Ongusaha P, Jahng WJ, Araki K, Choi CS et al (2005) Role of Rho-kinase in regulation of insulin action and glucose homeostasis. Cell Metab 2:119–129

    Article  CAS  PubMed  Google Scholar 

  69. Paz K, Liu YF, Shorer H, Hemi R, LeRoith D et al (1999) Phosphorylation of insulin receptor substrate-1 (IRS-1) by protein kinase B positively regulates IRS-1 function. J Biol Chem 274:28816–28822

    Article  CAS  PubMed  Google Scholar 

  70. Sesti G, Federici M, Hribal ML, Lauro D, Sbraccia P et al (2001) Defects of the insulin receptor substrate (IRS) system in human metabolic disorders. FASEB J 15:2099–2111

    Article  CAS  PubMed  Google Scholar 

  71. Araki E, Lipes MA, Patti M-E, Bruning JC, Haag BL III et al (1994) Alternative pathway of insulin signlaing in targeted disruption of the IRS-1 gene. Nature 372:186–190

    Article  CAS  PubMed  Google Scholar 

  72. Kubota N, Terauchi Y, Tobe K, Yano W, Suzuki R et al (2004) Insulin receptor substrate 2 plays a crucial role in beta cells and the hypothalamus. J Clin Invest 114:917–927

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Withers DJ, Gutierrez JS, Towery H, Burks DJ, Ren JM et al (1998) Disruption of IRS-2 causes type 2 diabetes in mice. Nature 391:900–904

    Article  CAS  PubMed  Google Scholar 

  74. Tseng YH, Butte AJ, Kokkotou E, Yechoor VK, Taniguchi CM et al (2005) Prediction of preadipocyte differentiation by gene expression reveals role of insulin receptor substrates and necdin. Nat Cell Biol 7:601–611

    Article  CAS  PubMed  Google Scholar 

  75. Miki H, Yamauchi T, Suzuki R, Komeda K, Tsuchida A et al (2001) Essential role of insulin receptor substrate 1 (IRS-1) and IRS-2 in adipocyte differentiation. Mol Cell Biol 21:2521–2532

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Chang Q, Li Y, White MF, Fletcher JA, Xiao S (2002) Constitutive activation of insulin receptor substrate 1 is a frequent event in human tumors: therapeutic implications. Cancer Res 62:6035–6038

    CAS  PubMed  Google Scholar 

  77. Koda M, Sulkowska M, Kanczuga-Koda L, Sulkowski S (2005) Expression of insulin receptor substrate 1 in primary breast cancer and lymph node metastases. J Clin Pathol 58:645–649

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Jackson JG, White MF, Yee D (1998) Insulin receptor substrate-1 is the predominant signaling molecule activated by insulin-like growth factor-I, insulin, and interleukin-4 in estrogen receptor-positive human breast cancer cells. J Biol Chem 273:9994–10003

    Article  CAS  PubMed  Google Scholar 

  79. Rocha RL, Hilsenbeck SG, Jackson JG, VanDenBerg CL, Weng C et al (1997) Insulin-like growth factor binding protein-3 and insulin receptor substrate-1 in breast cancer: correlation with clinical parameters and disease-free survival. Clin Cancer Res 3:103–109

    CAS  PubMed  Google Scholar 

  80. Dearth RK, Cui X, Kim HJ, Kuiatse I, Lawrence NA et al (2006) Mammary tumorigenesis and metastasis caused by overexpression of insulin receptor substrate 1 (IRS-1) or IRS-2. Mol Cell Biol 26:9302–9314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Asano T, Yao Y, Shin S, McCubrey J, Abbruzzese JL et al (2005) Insulin receptor substrate is a mediator of phosphoinositide 3-kinase activation in quiescent pancreatic cancer cells. Cancer Res 65:9164–9168

    Article  CAS  PubMed  Google Scholar 

  82. Longato L, de la Monte S, Kuzushita N, Horimoto M, Rogers AB et al (2009) Overexpression of insulin receptor substrate-1 and hepatitis Bx genes causes premalignant alterations in the liver. Hepatology 49:1935–1943

    Article  CAS  PubMed  Google Scholar 

  83. Tanaka S, Wands JR (1996) Insulin receptor substrate 1 overexpression in human hepatocellular carcinoma cells prevents transforming growth factor beta1-induced apoptosis. Cancer Res 56:3391–3394

    CAS  PubMed  Google Scholar 

  84. Boissan M, Beurel E, Wendum D, Rey C, Lecluse Y et al (2005) Overexpression of insulin receptor substrate-2 in human and murine hepatocellular carcinoma. Am J Pathol 167:869–877

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Tanaka S, Wands JR (1996) A carboxy-terminal truncated insulin receptor substrate-1 dominant negative protein reverses the human hepatocellular carcinoma malignant phenotype. J Clin Invest 98:2100–2108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Knowlden JM, Jones HE, Barrow D, Gee JM, Nicholson RI et al (2008) Insulin receptor substrate-1 involvement in epidermal growth factor receptor and insulin-like growth factor receptor signalling: implication for Gefitinib (‘Iressa’) response and resistance. Breast Cancer Res Treat 111:79–91

    Article  CAS  PubMed  Google Scholar 

  87. Citri A, Yarden Y (2006) EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol 7:505–516

    Article  CAS  PubMed  Google Scholar 

  88. Guix M, Faber AC, Wang SE, Olivares MG, Song Y et al (2008) Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins. J Clin Invest 118:2609–2619

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Nagle JA, Ma Z, Byrne MA, White MF, Shaw LM (2004) Involvement of insulin receptor substrate 2 in mammary tumor metastasis. Mol Cell Biol 24:9726–9735

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Szabolcs M, Keniry M, Simpson L, Reid LJ, Koujak S et al (2009) Irs2 inactivation suppresses tumor progression in Pten+/- mice. Am J Pathol 174:276–286

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Laustsen PG, Michael MD, Crute BE, Cohen SE, Ueki K et al (2002) Lipoatrophic diabetes in Irs1(−/−)/Irs3(−/−) double knockout mice. Genes Dev 16:3213–3222

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Karrman K, Kjeldsen E, Lassen C, Isaksson M, Davidsson J et al (2009) The t(X;7)(q22;q34) in paediatric T-cell acute lymphoblastic leukaemia results in overexpression of the insulin receptor substrate 4 gene through illegitimate recombination with the T-cell receptor beta locus. Br J Haematol 144:546–551

    Article  CAS  PubMed  Google Scholar 

  93. Fantin VR, Wang Q, Lienhard GE, Keller SR (2000) Mice lacking insulin receptor substrate 4 exhibit mild defects in growth, reproduction, and glucose homeostasis. Am J Physiol Endocrinol Metab 278:E127–E133

    Article  CAS  PubMed  Google Scholar 

  94. Taniguchi CM, Ueki K, Kahn R (2005) Complementary roles of IRS-1 and IRS-2 in the hepatic regulation of metabolism. J Clin Invest 115:718–727

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Sun XJ, Pons S, Wang LM, Zhang Y, Yenush L et al (1997) The IRS-2 gene on murine chromosome 8 encodes a unique signaling adapter for insulin and cytokine action. Mol Endocrinol 11:251–262

    Article  CAS  PubMed  Google Scholar 

  96. Inoue G, Cheatham B, Emkey R, Kahn CR (1998) 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

    Article  CAS  PubMed  Google Scholar 

  97. Sun H, Tu X, Prisco M, Wu A, Casiburi I et al (2003) Insulin-like growth factor I receptor signaling and nuclear translocation of insulin receptor substrates 1 and 2. Mol Endocrinol 17:472–486

    Article  CAS  PubMed  Google Scholar 

  98. Ogihara T, Shin BC, Anai M, Katagiri H, Inukai K et al (1997) 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

    Article  CAS  PubMed  Google Scholar 

  99. Sawka-Verhelle D, Tartare-Deckert S, White MF, Van Obberghen E (1996) 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

    Article  CAS  PubMed  Google Scholar 

  100. D’Ambrosio C, Keller SR, Morrione A, Lienhard GE, Baserga R et al (1995) Transforming potential of the insulin receptor substrate 1. Cell Growth Differ 6:557–562

    CAS  PubMed  Google Scholar 

  101. DeAngelis T, Chen J, Wu A, Prisco M, Baserga R (2006) Transformation by the simian virus 40 T antigen is regulated by IGF-I receptor and IRS-1 signaling. Oncogene 25:32–42

    Article  CAS  PubMed  Google Scholar 

  102. Tseng YH, Kriauciunas KM, Kokkotou E, Kahn CR (2004) Differential roles of insulin receptor substrates in brown adipocyte differentiation. Mol Cell Biol 24:1918–1929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Myers MG Jr, Backer JM, Sun XJ, Shoelson S, Hu P et al (1992) IRS-1 activates phosphatidylinositol 3′-kinase by associating with src homology 2 domains of p85. Proc Natl Acad Sci USA 89:10350–10354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Cheatham B, Vlahos CJ, Cheatham L, Wang L, Blenis J et al (1994) Phosphatidylinositol 3-kinase activation is required for insulin stimulation of pp 70 S6 kinase, DNA synthesis, and glucose transporter translocation. Mol Cell Biol 14:4902–4911

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Shepherd PR, Withers DJ, Siddle K (1998) Phosphoinositide 3-kinase: the key switch mechanism in insulin signalling. Biochem J 333(Pt 3):471–490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR et al (1997) Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol 7:261–269

    Article  CAS  PubMed  Google Scholar 

  107. Le Good JA, Ziegler WH, Parekh DB, Alessi DR, Cohen P et al (1998) Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1. Science 281:2042–2045

    Article  PubMed  Google Scholar 

  108. Woodgett JR (2005) Recent advances in the protein kinase B signaling pathway. Curr Opin Cell Biol 17:150–157

    Article  CAS  PubMed  Google Scholar 

  109. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307:1098–1101

    Article  CAS  PubMed  Google Scholar 

  110. Maehama T, Dixon JE (1999) PTEN: a tumour suppressor that functions as a phospholipid phosphatase. Trends Cell Biol 9:125–128

    Article  CAS  PubMed  Google Scholar 

  111. Nakashima N, Sharma PM, Imamura T, Bookstein R, Olefsky JM (2000) The tumor suppressor PTEN negatively regulates insulin signaling in 3T3-L1 adipocytes. J Biol Chem 275:12889–12895

    Article  CAS  PubMed  Google Scholar 

  112. Yao YJ, Ping XL, Zhang H, Chen FF, Lee PK et al (1999) PTEN/MMAC1 mutations in hepatocellular carcinomas. Oncogene 18:3181–3185

    Article  CAS  PubMed  Google Scholar 

  113. Schmitz KJ, Wohlschlaeger J, Lang H, Sotiropoulos GC, Malago M et al (2008) Activation of the ERK and AKT signalling pathway predicts poor prognosis in hepatocellular carcinoma and ERK activation in cancer tissue is associated with hepatitis C virus infection. J Hepatol 48:83–90

    Article  CAS  PubMed  Google Scholar 

  114. Vanhaesebroeck B, Welham MJ, Kotani K, Stein R, Warne PH et al (1997) P110delta, a novel phosphoinositide 3-kinase in leukocytes. Proc Natl Acad Sci USA 94:4330–4335

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Rodriguez-Viciana P, Warne PH, Dhand R, Vanhaesebroeck B, Gout I et al (1994) Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 370:527–532

    Article  CAS  PubMed  Google Scholar 

  116. Rizo J, Sudhof TC (1998) C2-domains, structure and function of a universal Ca2+-binding domain. J Biol Chem 273:15879–15882

    Article  CAS  PubMed  Google Scholar 

  117. Huang CH, Mandelker D, Schmidt-Kittler O, Samuels Y, Velculescu VE et al (2007) The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations. Science 318:1744–1748

    Article  CAS  PubMed  Google Scholar 

  118. Yu J, Zhang Y, McIlroy J, Rordorf-Nikolic T, Orr GA et al (1998) Regulation of the p85/p110 phosphatidylinositol 3’-kinase: stabilization and inhibition of the p110alpha catalytic subunit by the p85 regulatory subunit. Mol Cell Biol 18:1379–1387

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Chang HW, Aoki M, Fruman D, Auger KR, Bellacosa A et al (1997) Transformation of chicken cells by the gene encoding the catalytic subunit of PI 3-kinase. Science 276:1848–1850

    Article  CAS  PubMed  Google Scholar 

  120. Zhao JJ, Liu Z, Wang L, Shin E, Loda MF et al (2005) The oncogenic properties of mutant p110alpha and p110beta phosphatidylinositol 3-kinases in human mammary epithelial cells. Proc Natl Acad Sci USA 102:18443–18448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Miyake T, Yoshino K, Enomoto T, Takata T, Ugaki H et al (2008) PIK3CA gene mutations and amplifications in uterine cancers, identified by methods that avoid confounding by PIK3CA pseudogene sequences. Cancer Lett 261:120–126

    Article  CAS  PubMed  Google Scholar 

  122. Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J et al (2004) High frequency of mutations of the PIK3CA gene in human cancers. Science 304:554

    Article  CAS  PubMed  Google Scholar 

  123. Wu G, Xing M, Mambo E, Huang X, Liu J et al (2005) Somatic mutation and gain of copy number of PIK3CA in human breast cancer. Breast Cancer Res 7:R609–R616

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Campbell IG, Russell SE, Choong DY, Montgomery KG, Ciavarella ML et al (2004) Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res 64:7678–7681

    Article  CAS  PubMed  Google Scholar 

  125. Zhang A, Maner S, Betz R, Angstrom T, Stendahl U et al (2002) Genetic alterations in cervical carcinomas: frequent low-level amplifications of oncogenes are associated with human papillomavirus infection. Int J Cancer 101:427–433

    Article  CAS  PubMed  Google Scholar 

  126. Lee JW, Soung YH, Kim SY, Lee HW, Park WS et al (2005) PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas. Oncogene 24:1477–1480

    Article  CAS  PubMed  Google Scholar 

  127. Guo XN, Rajput A, Rose R, Hauser J, Beko A et al (2007) Mutant PIK3CA-bearing colon cancer cells display increased metastasis in an orthotopic model. Cancer Res 67:5851–5858

    Article  CAS  PubMed  Google Scholar 

  128. McLendon R, Friedman A, Bigner D, Van Meir EG, Brat DJ et al (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455(7216):1061–1068

    Article  CAS  Google Scholar 

  129. Miled N, Yan Y, Hon WC, Perisic O, Zvelebil M et al (2007) Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit. Science 317:239–242

    Article  CAS  PubMed  Google Scholar 

  130. Denley A, Kang S, Karst U, Vogt PK (2008) Oncogenic signaling of class I PI3K isoforms. Oncogene 27:2561–2574

    Article  CAS  PubMed  Google Scholar 

  131. Engelman JA, Chen L, Tan X, Crosby K, Guimaraes AR et al (2008) Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med 14:1351–1356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Foukas LC, Claret M, Pearce W, Okkenhaug K, Meek S et al (2006) Critical role for the p110alpha phosphoinositide-3-OH kinase in growth and metabolic regulation. Nature 441:366–370

    Article  CAS  PubMed  Google Scholar 

  133. Bi L, Okabe I, Bernard DJ, Wynshaw-Boris A, Nussbaum RL (1999) Proliferative defect and embryonic lethality in mice homozygous for a deletion in the p110alpha subunit of phosphoinositide 3-kinase. J Biol Chem 274:10963–10968

    Article  CAS  PubMed  Google Scholar 

  134. Bi L, Okabe I, Bernard DJ, Nussbaum RL (2002) Early embryonic lethality in mice deficient in the p110beta catalytic subunit of PI 3-kinase. Mamm Genome 13:169–172

    CAS  PubMed  Google Scholar 

  135. Asano T, Kanda A, Katagiri H, Nawano M, Ogihara T et al (2000) p110beta 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

    Article  CAS  PubMed  Google Scholar 

  136. Siddhanta U, McIlroy J, Shah A, Zhang Y, Backer JM (1998) Distinct roles for the p110alpha and hVPS34 phosphatidylinositol 3’-kinases in vesicular trafficking, regulation of the actin cytoskeleton, and mitogenesis. J Cell Biol 143:1647–1659

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Jia S, Liu Z, Zhang S, Liu P, Zhang L et al (2008) Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis. Nature 454:776–779

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Knight ZA, Gonzalez B, Feldman ME, Zunder ER, Goldenberg DD et al (2006) A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell 125:733–747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Graupera M, Guillermet-Guibert J, Foukas LC, Phng LK, Cain RJ et al (2008) Angiogenesis selectively requires the p110alpha isoform of PI3K to control endothelial cell migration. Nature 453:662–666

    Article  CAS  PubMed  Google Scholar 

  140. Wee S, Wiederschain D, Maira SM, Loo A, Miller C et al (2008) PTEN-deficient cancers depend on PIK3CB. Proc Natl Acad Sci USA 105:13057–13062

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Luo J, Cantley LC (2005) The negative regulation of phosphoinositide 3-kinase signaling by p85 and it’s implication in cancer. Cell Cycle 4:1309–1312

    Article  CAS  PubMed  Google Scholar 

  142. Engelman JA, Luo J, Cantley LC (2006) The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 7:606–619

    Article  CAS  PubMed  Google Scholar 

  143. Antonetti DA, Algenstaedt P, Kahn CR (1996) 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Ueki K, Yballe CM, Brachmann SM, Vicent D, Watt JM et al (2002) Increased insulin sensitivity in mice lacking p85beta subunit of phosphoinositide 3-kinase. Proc Natl Acad Sci USA 99:419–424

    Article  CAS  PubMed  Google Scholar 

  145. Geering B, Cutillas PR, Nock G, Gharbi SI, Vanhaesebroeck B (2007) Class IA phosphoinositide 3-kinases are obligate p85-p110 heterodimers. Proc Natl Acad Sci USA 104:7809–7814

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Zhang L, Huang J, Yang N, Greshock J, Liang S et al (2007) Integrative genomic analysis of phosphatidylinositol 3’-kinase family identifies PIK3R3 as a potential therapeutic target in epithelial ovarian cancer. Clin Cancer Res 13:5314–5321

    Article  CAS  PubMed  Google Scholar 

  147. Shekar SC, Wu H, Fu Z, Yip SC, Nagajyothi F et al (2005) Mechanism of constitutive phosphoinositide 3-kinase activation by oncogenic mutants of the p85 regulatory subunit. J Biol Chem 280:27850–27855

    Article  CAS  PubMed  Google Scholar 

  148. Jimenez C, Jones DR, Rodriguez-Viciana P, Gonzalez-Garcia A, Leonardo E et al (1998) Identification and characterization of a new oncogene derived from the regulatory subunit of phosphoinositide 3-kinase. EMBO J 17:743–753

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Philp AJ, Campbell IG, Leet C, Vincan E, Rockman SP et al (2001) The phosphatidylinositol 3’-kinase p85alpha gene is an oncogene in human ovarian and colon tumors. Cancer Res 61:7426–7429

    CAS  PubMed  Google Scholar 

  150. Almind K, Delahaye L, Hansen T, Van Obberghen E, Pedersen O et al (2002) Characterization of the Met326Ile variant of phosphatidylinositol 3-kinase p85alpha. Proc Natl Acad Sci USA 99:2124–2128

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Li L, Plummer SJ, Thompson CL, Tucker TC, Casey G (2008) Association between phosphatidylinositol 3-kinase regulatory subunit p85alpha Met326Ile genetic polymorphism and colon cancer risk. Clin Cancer Res 14:633–637

    Article  CAS  PubMed  Google Scholar 

  152. Richard F, Pacyna-Gengelbach M, Schluns K, Fleige B, Winzer KJ et al (2000) Patterns of chromosomal imbalances in invasive breast cancer. Int J Cancer 89:305–310

    Article  CAS  PubMed  Google Scholar 

  153. Tavassoli M, Steingrimsdottir H, Pierce E, Jiang X, Alagoz M et al (1996) Loss of heterozygosity on chromosome 5q in ovarian cancer is frequently accompanied by TP53 mutation and identifies a tumour suppressor gene locus at 5q13.1-21. Br J Cancer 74:115–119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Roque L, Rodrigues R, Pinto A, Moura-Nunes V, Soares J (2003) Chromosome imbalances in thyroid follicular neoplasms: a comparison between follicular adenomas and carcinomas. Genes Chromosom Cancer 36:292–302

    Article  CAS  PubMed  Google Scholar 

  155. Achille A, Baron A, Zamboni G, Di Pace C, Orlandini S et al (1998) Chromosome 5 allelic losses are early events in tumours of the papilla of Vater and occur at sites similar to those of gastric cancer. Br J Cancer 78:1653–1660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Katoh H, Shibata T, Kokubu A, Ojima H, Loukopoulos P et al (2005) Genetic profile of hepatocellular carcinoma revealed by array-based comparative genomic hybridization: identification of genetic indicators to predict patient outcome. J Hepatol 43:863–874

    Article  CAS  PubMed  Google Scholar 

  157. Mauvais-Jarvis F, Ueki K, Fruman DA, Hirshman MF, Sakamoto K et al (2002) Reduced expression of the murine p85alpha subunit of phosphoinositide 3-kinase improves insulin signaling and ameliorates diabetes. J Clin Invest 109:141–149

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Taniguchi CM, Tran TT, Kondo T, Luo J, Ueki K et al (2006) Phosphoinositide 3-kinase regulatory subunit p85alpha suppresses insulin action via positive regulation of PTEN. Proc Natl Acad Sci USA 103:12093–12097

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Luo J, Sobkiw CL, Logsdon NM, Watt JM, Signoretti S et al (2005) Modulation of epithelial neoplasia and lymphoid hyperplasia in PTEN+/- mice by the p85 regulatory subunits of phosphoinositide 3-kinase. Proc Natl Acad Sci USA 102:10238–10243

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Ueki K, Fruman DA, Brachmann SM, Tseng YH, Cantley LC et al (2002) Molecular balance between the regulatory and catalytic subunits of phosphoinositide 3-kinase regulates cell signaling and survival. Mol Cell Biol 22:965–977

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Barbour LA, Mizanoor Rahman S, Gurevich I, Leitner JW, Fischer SJ et al (2005) Increased P85alpha is a potent negative regulator of skeletal muscle insulin signaling and induces in vivo insulin resistance associated with growth hormone excess. J Biol Chem 280:37489–37494

    Article  CAS  PubMed  Google Scholar 

  162. Luo J, Field SJ, Lee JY, Engelman JA, Cantley LC (2005) The p85 regulatory subunit of phosphoinositide 3-kinase down-regulates IRS-1 signaling via the formation of a sequestration complex. J Cell Biol 170(3):455–464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Pollak M (2008) Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 8:915–928

    Article  CAS  PubMed  Google Scholar 

  164. Yuan TL, Cantley LC (2008) PI3K pathway alterations in cancer: variations on a theme. Oncogene 27:5497–5510

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Medicine, Joslin Diabetes Center, Harvard Medical School, Boston, MA, 02215, USA

    Cullen M. Taniguchi & C. Ronald Kahn

  2. Division of Signal Transduction, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA

    C. Ronald Kahn

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    I. George Fantus

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Taniguchi, C.M., Kahn, C.R. (2011). Insulin/IGF-1 Signaling Nodes and their Role in Carcinogenesis. In: Fantus, I. (eds) Insulin Resistance and Cancer. Energy Balance and Cancer, vol 1. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-9911-5_2

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