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The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism

Key Points

  • Phosphatidylinositol 3-kinases (PI3Ks) are members of a unique and conserved family of intracellular lipid kinases that phosphorylate the 3′-hydroxyl group of phosphatidylinositols. This reaction leads to the activation of many intracellular signalling pathways that regulate functions as diverse as cell metabolism, survival and polarity, and vesicle trafficking.

  • PI3Ks are grouped into three classes (I–III) according to their substrate preference and sequence homology. Different classes of PI3K have distinct roles in cellular signal transduction, as do the different isoforms that can exist within each class.

  • Studies using mouse models have shown the importance of class IA PI3K signalling in regulating growth and metabolism.

  • Attenuated PI3K signalling downstream of the insulin receptor is a main contributor towards type-2 diabetes, whereas mutations that lead to the amplification of PI3K signalling are among the most common mutations in human cancers.

  • Many types of human cancer harbour mutations in key proteins that regulate the amount of phosphatidylinositol-3,4,5-trisphosphate (PIP3) generated at the membrane. The two most commonly mutated genes are the mammalian phosphatase and tensin homologue (PTEN) and phosphoinositide-3-kinase, catalytic, α polypeptide (PIK3CA).

  • In normal cells, negative-feedback loops function to attenuate PI3K signalling. One such pathway is the mammalian target of rapamycin (mTOR)–raptor-dependent pathway that disrupts insulin receptor substrate (IRS)-mediated PI3K activation.

  • As isoform-specific inhibitors of the PI3K pathway are developed as potential therapeutics, careful pre-clinical studies using floxed alleles, RNA interference and mutated inhibitor-resistant kinases will be required to distinguish between their on- and off-target effects.

Abstract

Phosphatidylinositol 3-kinases (PI3Ks) evolved from a single enzyme that regulates vesicle trafficking in unicellular eukaryotes into a family of enzymes that regulate cellular metabolism and growth in multicellular organisms. In this review, we examine how the PI3K pathway has evolved to control these fundamental processes, and how this pathway is in turn regulated by intricate feedback and crosstalk mechanisms. In light of the recent advances in our understanding of the function of PI3Ks in the pathogenesis of diabetes and cancer, we discuss the exciting therapeutic opportunities for targeting this pathway to treat these diseases.

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Figure 1: Mechanisms of class I phosphatidylinositol 3-kinase (PI3K) activation.
Figure 2: The insulin–phosphatidylinositol 3-kinase (PI3K) signalling pathway is conserved in eukaryotic evolution.
Figure 3: Rapamycin-sensitive feedback on phosphatidylinositol 3-kinase (PI3K) signalling.

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References

  1. Cantley, L. C. The phosphoinositide 3-kinase pathway. Science 296, 1655–1657 (2002).

    Article  CAS  PubMed  Google Scholar 

  2. Katso, R. et al. Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annu. Rev. Cell Dev. Biol. 17, 615–675 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Wymann, M. P. et al. Phosphoinositide 3-kinase γ: a key modulator in inflammation and allergy. Biochem. Soc. Trans. 31, 275–280 (2003).

    Article  CAS  PubMed  Google Scholar 

  4. Stephens, L. R. et al. The Gβγsensitivity of a PI3K is dependent upon a tightly associated adaptor, p101. Cell 89, 105–114 (1997).

    Article  CAS  PubMed  Google Scholar 

  5. Suire, S. et al. p84, a new Gβγ-activated regulatory subunit of the type IB phosphoinositide 3-kinase p110γ. Curr. Biol. 15, 566–570 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. Voigt, P., Dorner, M. B. & Schaefer, M. Characterization of p87PIKAP, a novel regulatory subunit of phosphoinositide 3-kinase γ that is highly expressed in heart and interacts with PDE3B. J. Biol. Chem. 281, 9977–9986 (2006).

    Article  CAS  PubMed  Google Scholar 

  7. Gaidarov, I., Smith, M. E., Domin, J. & Keen, J. H. The class II phosphoinositide 3-kinase C2α is activated by clathrin and regulates clathrin-mediated membrane trafficking. Mol. Cell 7, 443–449 (2001).

    Article  CAS  PubMed  Google Scholar 

  8. Odorizzi, G., Babst, M. & Emr, S. D. Phosphoinositide signaling and the regulation of membrane trafficking in yeast. Trends Biochem. Sci. 25, 229–235 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. Byfield, M. P., Murray, J. T. & Backer, J. M. hVps34 is a nutrient-regulated lipid kinase required for activation of p70 S6 kinase. J. Biol. Chem. 280, 33076–33082 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. Nobukuni, T. et al. Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase. Proc. Natl Acad. Sci. USA 102, 14238–14243 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wurmser, A. E. & Emr, S. D. Novel PtdIns(3)P-binding protein Etf1 functions as an effector of the Vps34 PtdIns 3-kinase in autophagy. J. Cell Biol. 158, 761–772 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kihara, A., Noda, T., Ishihara, N. & Ohsumi, Y. Two distinct Vps34 phosphatidylinositol 3-kinase complexes function in autophagy and carboxypeptidase Y sorting in Saccharomyces cerevisiae. J. Cell Biol. 152, 519–530 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Stein, R. Prospects of phosphoinositide 3-kinase inhibition as a cancer treatment. Endocr. Relat. Cancer 8, 237–248 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. Van Haastert, P. & Devreotes, P. Chemotaxis: signalling the way forward. Nature Rev. Mol. Cell Biol. 5, 626–634 (2004).

    Article  CAS  Google Scholar 

  15. Herman, P. K., Stack, J. H., DeModena, J. A. & Emr, S. D. A novel protein kinase homolog essential for protein sorting to the yeast lysosome-like vacuole. Cell 64, 425–437 (1991).

    Article  CAS  PubMed  Google Scholar 

  16. Stack, J. H., Herman, P. K., Schu, P. V. & Emr, S. D. A membrane-associated complex containing the Vps15 protein kinase and the Vps34 PI 3-kinase is essential for protein sorting to the yeast lysosome-like vacuole. EMBO J. 12, 2195–2204 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. DiNitto, J. P., Cronin, T. C. & Lambright, D. G. Membrane recognition and targeting by lipid-binding domains. Sci. STKE 2003, re16 (2003).

    PubMed  Google Scholar 

  18. Brown, W. J., DeWald, D. B., Emr, S. D., Plutner, H. & Balch, W. E. Role for phosphatidylinositol 3-kinase in the sorting and transport of newly synthesized lysosomal enzymes in mammalian cells. J. Cell Biol. 130, 781–796 (1995).

    Article  CAS  PubMed  Google Scholar 

  19. Mitra, P. et al. A novel phosphatidylinositol(3,4,5)P3 pathway in fission yeast. J. Cell Biol. 166, 205–211 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Friedman, D. B. & Johnson, T. E. A mutation in the age-1 gene in Caenorhabditis elegans lengthens life and reduces hermaphrodite fertility. Genetics 118, 75–86 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Kenyon, C., Chang, J., Gensch, E., Rudner, A. & Tabtiang, R. A C. elegans mutant that lives twice as long as wild type. Nature 366, 461–464 (1993).

    Article  CAS  PubMed  Google Scholar 

  22. Wolkow, C. A., Munoz, M. J., Riddle, D. L. & Ruvkun, G. Insulin receptor substrate and p55 orthologous adaptor proteins function in the Caenorhabditis elegans daf-2/insulin-like signaling pathway. J. Biol. Chem. 277, 49591–49597 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Ogg, S. & Ruvkun, G. The C. elegans PTEN homolog, DAF-18, acts in the insulin receptor-like metabolic signaling pathway. Mol. Cell 2, 887–893 (1998).

    Article  CAS  PubMed  Google Scholar 

  24. Guarente, L. & Kenyon, C. Genetic pathways that regulate ageing in model organisms. Nature 408, 255–262 (2000).

    Article  CAS  PubMed  Google Scholar 

  25. Oldham, S. & Hafen, E. Insulin/IGF and target of rapamycin signaling: a TOR de force in growth control. Trends Cell Biol. 13, 79–85 (2003).

    Article  CAS  PubMed  Google Scholar 

  26. Bateman, J. M. & McNeill, H. Temporal control of differentiation by the insulin receptor/tor pathway in Drosophila. Cell 119, 87–96 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Inoki, K., Li, Y., Zhu, T., Wu, J. & Guan, K. L. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nature Cell Biol. 4, 648–657 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. Potter, C. J., Pedraza, L. G. & Xu, T. Akt regulates growth by directly phosphorylating Tsc2. Nature Cell Biol. 4, 658–665 (2002). References 27 and 28, along with the study in reference 115, show that AKT regulates mTOR activity by directly phosphorylating tuberin.

    Article  CAS  PubMed  Google Scholar 

  29. Junger, M. A. et al. The Drosophila forkhead transcription factor FOXO mediates the reduction in cell number associated with reduced insulin signaling. J. Biol. 2, 20 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  30. Taniguchi, C. M., Emanuelli, B. & Kahn, C. R. Critical nodes in signalling pathways: insights into insulin action. Nature Rev. Mol. Cell Biol. 7, 85–96 (2006).

    Article  CAS  Google Scholar 

  31. Katome, T. et al. Use of RNA interference-mediated gene silencing and adenoviral overexpression to elucidate the roles of AKT/protein kinase B isoforms in insulin actions. J. Biol. Chem. 278, 28312–28323 (2003).

    Article  CAS  PubMed  Google Scholar 

  32. 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 

  33. Thong, F. S., Dugani, C. B. & Klip, A. Turning signals on and off: GLUT4 traffic in the insulin-signaling highway. Physiology (Bethesda) 20, 271–284 (2005).

    CAS  Google Scholar 

  34. Brachmann, S. M., Ueki, K., Engelman, J. A., Kahn, R. C. & Cantley, L. C. Phosphoinositide 3-kinase catalytic subunit deletion and regulatory subunit deletion have opposite effects on insulin sensitivity in mice. Mol. Cell. Biol. 25, 1596–1607 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Foukas, L. C. et al. Critical role for the p110α phosphoinositide-3-OH kinase in growth and metabolic regulation. Nature 441, 366–370 (2006).

    Article  CAS  PubMed  Google Scholar 

  36. Kurlawalla-Martinez, C. et al. Insulin hypersensitivity and resistance to streptozotocin-induced diabetes in mice lacking PTEN in adipose tissue. Mol. Cell. Biol. 25, 2498–2510 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ueki, K. et al. Positive and negative roles of p85α and p85β regulatory subunits of phosphoinositide 3-kinase in insulin signaling. J. Biol. Chem. 278, 48453–48466 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. 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 

  39. Luo, J. et al. Loss of class IA PI3K signaling in muscle leads to impaired muscle growth, insulin response, and hyperlipidemia. Cell Metab. 3, 355–366 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Taniguchi, C. M. et al. Divergent regulation of hepatic glucose and lipid metabolism by phosphoinositide 3-kinase via Akt and PKCλ/ζ. Cell Metab. 3, 343–353 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. Saltiel, A. R. & Kahn, C. R. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414, 799–806 (2001).

    Article  CAS  PubMed  Google Scholar 

  42. Shulman, G. I. Unraveling the cellular mechanism of insulin resistance in humans: new insights from magnetic resonance spectroscopy. Physiology (Bethesda) 19, 183–190 (2004).

    CAS  Google Scholar 

  43. Hansen, T. et al. Identification of a common amino acid polymorphism in the p85α regulatory subunit of phosphatidylinositol 3-kinase: effects on glucose disappearance constant, glucose effectiveness, and the insulin sensitivity index. Diabetes 46, 494–501 (1997).

    Article  CAS  PubMed  Google Scholar 

  44. Barroso, I. et al. Candidate gene association study in type 2 diabetes indicates a role for genes involved in β-cell function as well as insulin action. PLoS Biol. 1, e20 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  45. 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).

    Article  CAS  PubMed  Google Scholar 

  46. Barbour, L. et al. Increased p85α 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 (2005).

    Article  CAS  PubMed  Google Scholar 

  47. Kirwan, J. P. et al. Reversal of insulin resistance postpartum is linked to enhanced skeletal muscle insulin signaling. J. Clin. Endocrinol. Metab. 89, 4678–4684 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Bandyopadhyay, G., Yu, J., Ofrecio, J. & Olefsky, J. Increased p85/55/50 expression and decreased phosphotidylinositol 3-kinase activity in insulin-resistant human skeletal muscle. Diabetes 54, 2351–2359 (2005).

    Article  CAS  PubMed  Google Scholar 

  49. Gual, P., Le Marchand-Brustel, Y. & Tanti, J. Positive and negative regulation of insulin signaling through IRS-1 phosphorylation. Biochimie 87, 99–109 (2005).

    Article  CAS  PubMed  Google Scholar 

  50. 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 

  51. 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 

  52. Knight, Z. A. et al. A pharmacological map of the PI3-K family defines a role for p110α in insulin signaling. Cell 125, 733–747 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. LeRoith, D., Werner, H., Neuenschwander, S., Kalebic, T. & Helman, L. J. The role of the insulin-like growth factor-I receptor in cancer. Ann. NY Acad. Sci. 766, 402–408 (1995).

    Article  CAS  PubMed  Google Scholar 

  54. Liu, J. P., Baker, J., Perkins, A. S., Robertson, E. J. & Efstratiadis, A. Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell 75, 59–72 (1993).

    CAS  PubMed  Google Scholar 

  55. Dupont, J. & LeRoith, D. Insulin and insulin-like growth factor I receptors: similarities and differences in signal transduction. Horm. Res. 55 (Suppl. 2), 22–26 (2001).

    CAS  PubMed  Google Scholar 

  56. McMullen, J. R. et al. The insulin-like growth factor 1 receptor induces physiological heart growth via the phosphoinositide 3-kinase(p110α) pathway. J. Biol. Chem. 279, 4782–4793 (2004).

    Article  CAS  PubMed  Google Scholar 

  57. Shioi, T. et al. The conserved phosphoinositide 3-kinase pathway determines heart size in mice. EMBO J. 19, 2537–2548 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Shioi, T. et al. Akt/protein kinase B promotes organ growth in transgenic mice. Mol. Cell. Biol. 22, 2799–2809 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Luo, J. et al. Class IA phosphoinositide 3-kinase regulates heart size and physiological cardiac hypertrophy. Mol. Cell. Biol. 25, 9491–9502 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Backman, S. A. et al. Deletion of Pten in mouse brain causes seizures, ataxia and defects in soma size resembling Lhermitte–Duclos disease. Nature Genet. 29, 396–403 (2001).

    Article  CAS  PubMed  Google Scholar 

  61. Groszer, M. et al. Negative regulation of neural stem/progenitor cell proliferation by the Pten tumor suppressor gene in vivo. Science 294, 2186–2189 (2001).

    Article  CAS  PubMed  Google Scholar 

  62. Kwon, J. et al. Reversible oxidation and inactivation of the tumor suppressor PTEN in cells stimulated with peptide growth factors. Proc. Natl Acad. Sci. USA 101, 16419–16424 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Crackower, M. A. et al. Regulation of myocardial contractility and cell size by distinct PI3K–PTEN signaling pathways. Cell 110, 737–749 (2002).

    Article  CAS  PubMed  Google Scholar 

  64. Yang, Z. Z. et al. Physiological functions of protein kinase B/Akt. Biochem. Soc. Trans. 32, 350–354 (2004).

    Article  CAS  PubMed  Google Scholar 

  65. Sugimoto, Y., Whitman, M., Cantley, L. C. & Erikson, R. L. Evidence that the Rous sarcoma virus transforming gene product phosphorylates phosphatidylinositol and diacylglycerol. Proc. Natl Acad. Sci. USA 81, 2117–2121 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Whitman, M., Kaplan, D. R., Schaffhausen, B., Cantley, L. & Roberts, T. M. Association of phosphatidylinositol kinase activity with polyoma middle-T competent for transformation. Nature 315, 239–242 (1985).

    Article  CAS  PubMed  Google Scholar 

  67. Serunian, L. A., Auger, K. R., Roberts, T. M. & Cantley, L. C. Production of novel polyphosphoinositides in vivo is linked to cell transformation by polyomavirus middle T antigen. J. Virol. 64, 4718–4725 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. Chang, H. W. et al. Transformation of chicken cells by the gene encoding the catalytic subunit of PI 3-kinase. Science 276, 1848–1850 (1997).

    Article  CAS  PubMed  Google Scholar 

  69. Li, J. et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 275, 1943–1947 (1997).

    Article  CAS  PubMed  Google Scholar 

  70. Steck, P. A. et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nature Genet. 15, 356–362 (1997). References 69 and 70 identify PTEN as a candidate tumour suppressor.

    Article  CAS  PubMed  Google Scholar 

  71. Maehama, T. & Dixon, J. E. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J. Biol. Chem. 273, 13375–13378 (1998). This study shows that the PTEN tumour suppressor functions as a lipid phosphatase that dephosphorylates PIP 3.

    Article  CAS  PubMed  Google Scholar 

  72. Sansal, I. & Sellers, W. R. The biology and clinical relevance of the PTEN tumor suppressor pathway. J. Clin. Oncol. 22, 2954–2963 (2004).

    Article  CAS  PubMed  Google Scholar 

  73. Trotman, L. C. et al. Pten dose dictates cancer progression in the prostate. PLoS Biol. 1, e59 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Parsons, R. Human cancer, PTEN and the PI-3 kinase pathway. Semin. Cell Dev. Biol. 15, 171–176 (2004).

    Article  CAS  PubMed  Google Scholar 

  75. Wang, S. et al. Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer. Cancer Cell 4, 209–221 (2003).

    Article  CAS  PubMed  Google Scholar 

  76. Di Cristofano, A. et al. Impaired Fas response and autoimmunity in Pten+/− mice. Science 285, 2122–2125 (1999).

    Article  CAS  PubMed  Google Scholar 

  77. Suzuki, A. et al. T cell-specific loss of Pten leads to defects in central and peripheral tolerance. Immunity 14, 523–534 (2001).

    Article  CAS  PubMed  Google Scholar 

  78. Samuels, Y. et al. High frequency of mutations of the PIK3CA gene in human cancers. Science 304, 554 (2004). Reports the discovery that somatic mutations in the PIK3CA gene are a common event in human cancers.

    Article  CAS  PubMed  Google Scholar 

  79. Bader, A. G., Kang, S., Zhao, L. & Vogt, P. K. Oncogenic PI3K deregulates transcription and translation. Nature Rev. Cancer 5, 921–929 (2005).

    Article  CAS  Google Scholar 

  80. Kang, S., Bader, A. G. & Vogt, P. K. Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc. Natl Acad. Sci. USA 102, 802–807 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Isakoff, S. J. et al. Breast cancer-associated PIK3CA mutations are oncogenic in mammary epithelial cells. Cancer Res. 65, 10992–11000 (2005).

    Article  CAS  PubMed  Google Scholar 

  82. Samuels, Y. et al. Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell 7, 561–573 (2005).

    Article  CAS  PubMed  Google Scholar 

  83. Zhao, J. J. et al. The oncogenic properties of p110α and p110β phosphatidylinositol 3-kinases in human mammary epithelial cells. Proc. Natl Acad. Sci. USA 102, 18443–18448 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Bellacosa, A. et al. Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int. J. Cancer 64, 280–285 (1995).

    Article  CAS  PubMed  Google Scholar 

  85. Cheng, J. et al. Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc. Natl Acad. Sci. USA 93, 3636–3641 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Ruggeri, B., Huang, L., Wood, M., Cheng, J. & Testa, J. Amplification and overexpression of the AKT2 oncogene in a subset of human pancreatic ductal adenocarcinomas. Mol. Carcinog. 21, 81–86 (1998).

    Article  CAS  PubMed  Google Scholar 

  87. Parsons, D. W. et al. Colorectal cancer: mutations in a signalling pathway. Nature 436, 792 (2005).

    Article  CAS  PubMed  Google Scholar 

  88. Radimerski, T., Montagne, J., Hemmings-Mieszczak, M. & Thomas, G. Lethality of Drosophila lacking TSC tumor suppressor function rescued by reducing dS6K signaling. Genes Dev. 16, 2627–2632 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Manning, B. D. Balancing Akt with S6K: implications for both metabolic diseases and tumorigenesis. J. Cell Biol. 167, 399–403 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Harrington, L. S., Findlay, G. M. & Lamb, R. F. Restraining PI3K: mTOR signalling goes back to the membrane. Trends Biochem. Sci. 30, 35–42 (2005).

    Article  CAS  PubMed  Google Scholar 

  91. Aguirre, V., Uchida, T., Yenush, L., Davis, R. & White, M. The c-Jun NH2-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser307. J. Biol. Chem. 275, 9047–9054 (2000).

    Article  CAS  PubMed  Google Scholar 

  92. Hirosumi, J. et al. A central role for JNK in obesity and insulin resistance. Nature 420, 333–336 (2002).

    Article  CAS  PubMed  Google Scholar 

  93. Kim, J. et al. PKC-β knockout mice are protected from fat-induced insulin resistance. J. Clin. Invest. 114, 823–827 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Um, S. H. et al. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 431, 200–205 (2004).

    Article  CAS  PubMed  Google Scholar 

  95. Manning, B. D. et al. Feedback inhibition of Akt signaling limits the growth of tumors lacking Tsc2. Genes Dev. 19, 1773–1778 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. O'Reilly, K. E. et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 66, 1500–1508 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Engelman, J. A. et al. ErbB-3 mediates phosphoinositide 3-kinase activity in gefitinib-sensitive non-small cell lung cancer cell lines. Proc. Natl Acad. Sci. USA 102, 3788–3793 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Kaneto, H. et al. Possible novel therapy for diabetes with cell-permeable JNK-inhibitory peptide. Nature Med. 10, 1128–1132 (2004).

    Article  CAS  PubMed  Google Scholar 

  99. Alloatti, G., Montrucchio, G., Lembo, G. & Hirsch, E. Phosphoinositide 3-kinase γ: kinase-dependent and -independent activities in cardiovascular function and disease. Biochem. Soc. Trans. 32, 383–386 (2004).

    Article  CAS  PubMed  Google Scholar 

  100. Kobayashi, S. et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 352, 786–792 (2005).

    Article  CAS  PubMed  Google Scholar 

  101. Fruman, D. A., Meyers, R. E. & Cantley, L. C. Phosphoinositide kinases. Annu. Rev. Biochem. 67, 481–507 (1998).

    Article  CAS  PubMed  Google Scholar 

  102. Songyang, Z. et al. SH2 domains recognize specific phosphopeptide sequences. Cell 72, 767–778 (1993).

    Article  CAS  PubMed  Google Scholar 

  103. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Yu, J., Wjasow, C. & Backer, J. M. Regulation of the p85/p110α phosphatidylinositol 3′-kinase. Distinct roles for the N-terminal and C-terminal SH2 domains. J. Biol. Chem. 273, 30199–30203 (1998).

    Article  CAS  PubMed  Google Scholar 

  105. Franke, T. F., Kaplan, D. R., Cantley, L. C. & Toker, A. Direct regulation of the Akt proto-oncogene product by phosphatidylinositol-3,4-bisphosphate. Science 275, 665–668 (1997).

    Article  CAS  PubMed  Google Scholar 

  106. Klippel, A., Kavanaugh, W. M., Pot, D. & Williams, L. T. A specific product of phosphatidylinositol 3-kinase directly activates the protein kinase Akt through its pleckstrin homology domain. Mol. Cell. Biol. 17, 338–344 (1997). References 105 and 106 report the finding that AKT is activated on binding to the lipid products of PI3K.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. 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). Identifies the mTOR/rictor complex as the kinase that phosphorylates Ser473 of AKT.

    Article  CAS  PubMed  Google Scholar 

  108. Mora, A., Komander, D., van Aalten, D. M. & Alessi, D. R. PDK1, the master regulator of AGC kinase signal transduction. Semin. Cell Dev. Biol. 15, 161–170 (2004).

    Article  CAS  PubMed  Google Scholar 

  109. Cohen, P. & Frame, S. The renaissance of GSK3. Nature Rev. Mol. Cell Biol. 2, 769–776 (2001).

    Article  CAS  Google Scholar 

  110. Berwick, D., Hers, I., Heesom, K., Moule, S. & Tavare, J. The identification of ATP-citrate lyase as a protein kinase B (Akt) substrate in primary adipocytes. J. Biol. Chem. 277, 33895–33900 (2002).

    Article  CAS  PubMed  Google Scholar 

  111. Barthel, A., Schmoll, D. & Unterman, T. G. FoxO proteins in insulin action and metabolism. Trends Endocrinol. Metab. 16, 183–189 (2005).

    Article  CAS  PubMed  Google Scholar 

  112. Burgering, B. M. & Medema, R. H. Decisions on life and death: FOXO forkhead transcription factors are in command when PKB/Akt is off duty. J. Leukoc. Biol. 73, 689–701 (2003).

    Article  CAS  PubMed  Google Scholar 

  113. Vivanco, I. & Sawyers, C. L. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nature Rev. Cancer 2, 489–501 (2002).

    Article  CAS  Google Scholar 

  114. Richardson, C. J., Schalm, S. S. & Blenis, J. PI3-kinase and TOR: PIKTORing cell growth. Semin. Cell Dev. Biol. 15, 147–159 (2004).

    Article  CAS  PubMed  Google Scholar 

  115. Manning, B. D., Tee, A. R., Logsdon, M. N., Blenis, J. & Cantley, L. C. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol. Cell 10, 151–162 (2002).

    Article  CAS  PubMed  Google Scholar 

  116. Majumder, P. K. et al. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nature Med. 10, 594–601 (2004).

    Article  CAS  PubMed  Google Scholar 

  117. Neshat, M. S. et al. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. Proc. Natl Acad. Sci. USA 98, 10314–10319 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Podsypanina, K. et al. An inhibitor of mTOR reduces neoplasia and normalizes p70/S6 kinase activity in Pten +/− mice. Proc. Natl Acad. Sci. USA 98, 10320–10325 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Sarbassov dos, D., Ali, S. M. & Sabatini, D. M. Growing roles for the mTOR pathway. Curr. Opin. Cell Biol. 17, 596–603 (2005).

    Article  CAS  PubMed  Google Scholar 

  120. Datta, S. R. et al. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91, 231–241 (1997).

    Article  CAS  PubMed  Google Scholar 

  121. del Peso, L., Gonzalez-Garcia, M., Page, C., Herrera, R. & Nunez, G. Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science 278, 687–689 (1997).

    Article  CAS  PubMed  Google Scholar 

  122. Datta, S. R. et al. 14-3-3 proteins and survival kinases cooperate to inactivate BAD by BH3 domain phosphorylation. Mol. Cell 6, 41–51 (2000).

    Article  CAS  PubMed  Google Scholar 

  123. Zha, J., Harada, H., Yang, E., Jockel, J. & Korsmeyer, S. J. Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-XL . Cell 87, 619–628 (1996).

    Article  CAS  PubMed  Google Scholar 

  124. Accili, D. & Arden, K. C. Foxos at the crossroads of cellular metabolism, differentiation, and transformation. Cell 117, 421–426 (2004).

    Article  CAS  PubMed  Google Scholar 

  125. So, C. W. & Cleary, M. L. Common mechanism for oncogenic activation of MLL by forkhead family proteins. Blood 101, 633–639 (2003).

    Article  CAS  PubMed  Google Scholar 

  126. Wu, G. et al. Somatic mutation and gain of copy number of PIK3CA in human breast cancer. Breast Cancer Res. 7, R609–R616 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Levine, D. A. et al. Frequent mutation of the PIK3CA gene in ovarian and breast cancers. Clin. Cancer Res. 11, 2875–2878 (2005).

    Article  CAS  PubMed  Google Scholar 

  128. Lee, J. W. et al. PIK3CA gene is frequently mutated in breast carcinomas and hepatocellular carcinomas. Oncogene 24, 1477–1480 (2005).

    Article  CAS  PubMed  Google Scholar 

  129. Bachman, K. E. et al. The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol. Ther. 3, 772–775 (2004).

    Article  CAS  PubMed  Google Scholar 

  130. Campbell, I. G. et al. Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res. 64, 7678–7681 (2004).

    Article  CAS  PubMed  Google Scholar 

  131. Saal, L. H. et al. PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res. 65, 2554–2559 (2005).

    Article  CAS  PubMed  Google Scholar 

  132. Velho, S. et al. The prevalence of PIK3CA mutations in gastric and colon cancer. Eur. J. Cancer 41, 1649–1654 (2005).

    Article  CAS  PubMed  Google Scholar 

  133. Hartmann, C., Bartels, G., Gehlhaar, C., Holtkamp, N. & von Deimling, A. PIK3CA mutations in glioblastoma multiforme. Acta Neuropathol. (Berl.) 109, 639–642 (2005).

    Article  CAS  Google Scholar 

  134. Knobbe, C. B., Trampe-Kieslich, A. & Reifenberger, G. Genetic alteration and expression of the phosphoinositol-3-kinase/Akt pathway genes PIK3CA and PIKE in human glioblastomas. Neuropathol. Appl. Neurobiol. 31, 486–490 (2005).

    Article  CAS  PubMed  Google Scholar 

  135. Li, V. S. et al. Mutations of PIK3CA in gastric adenocarcinoma. BMC Cancer 5, 29 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Pedrero, J. M. et al. Frequent genetic and biochemical alterations of the PI 3-K/AKT/PTEN pathway in head and neck squamous cell carcinoma. Int. J. Cancer 114, 242–248 (2005).

    Article  CAS  PubMed  Google Scholar 

  137. Woenckhaus, J. et al. Genomic gain of PIK3CA and increased expression of p110α are associated with progression of dysplasia into invasive squamous cell carcinoma. J. Pathol. 198, 335–342 (2002).

    Article  CAS  PubMed  Google Scholar 

  138. Wu, G. et al. Uncommon mutation, but common amplifications, of the PIK3CA gene in thyroid tumors. J. Clin. Endocrinol. Metab. 90, 4688–4693 (2005).

    Article  CAS  PubMed  Google Scholar 

  139. Massion, P. P. et al. Genomic copy number analysis of non-small cell lung cancer using array comparative genomic hybridization: implications of the phosphatidylinositol 3-kinase pathway. Cancer Res. 62, 3636–3640 (2002).

    CAS  PubMed  Google Scholar 

  140. Bjorkqvist, A. M. et al. DNA gains in 3q occur frequently in squamous cell carcinoma of the lung, but not in adenocarcinoma. Genes Chromosomes Cancer 22, 79–82 (1998).

    Article  CAS  PubMed  Google Scholar 

  141. Byun, D. S. et al. Frequent monoallelic deletion of PTEN and its reciprocal association with PIK3CA amplification in gastric carcinoma. Int. J. Cancer 104, 318–327 (2003).

    Article  CAS  PubMed  Google Scholar 

  142. Miller, C. T. et al. Gene amplification in esophageal adenocarcinomas and Barrett's with high-grade dysplasia. Clin. Cancer Res. 9, 4819–4825 (2003).

    CAS  PubMed  Google Scholar 

  143. Ma, Y. Y. et al. PIK3CA as an oncogene in cervical cancer. Oncogene 19, 2739–2744 (2000).

    Article  CAS  PubMed  Google Scholar 

  144. Chiariello, E., Roz, L., Albarosa, R., Magnani, I. & Finocchiaro, G. PTEN/MMAC1 mutations in primary glioblastomas and short-term cultures of malignant gliomas. Oncogene 16, 541–545 (1998).

    Article  CAS  PubMed  Google Scholar 

  145. Wang, S. I. et al. Somatic mutations of PTEN in glioblastoma multiforme. Cancer Res. 57, 4183–4186 (1997).

    CAS  PubMed  Google Scholar 

  146. Smith, J. S. et al. PTEN mutation, EGFR amplification, and outcome in patients with anaplastic astrocytoma and glioblastoma multiforme. J. Natl Cancer Inst. 93, 1246–1256 (2001).

    Article  CAS  PubMed  Google Scholar 

  147. Cairns, P. et al. Frequent inactivation of PTEN/MMAC1 in primary prostate cancer. Cancer Res. 57, 4997–5000 (1997).

    CAS  PubMed  Google Scholar 

  148. Feilotter, H. E., Nagai, M. A., Boag, A. H., Eng, C. & Mulligan, L. M. Analysis of PTEN and the 10q23 region in primary prostate carcinomas. Oncogene 16, 1743–1748 (1998).

    Article  CAS  PubMed  Google Scholar 

  149. Pesche, S. et al. PTEN/MMAC1/TEP1 involvement in primary prostate cancers. Oncogene 16, 2879–2883 (1998).

    Article  CAS  PubMed  Google Scholar 

  150. Gray, I. C. et al. Mutation and expression analysis of the putative prostate tumour-suppressor gene PTEN. Br. J. Cancer 78, 1296–1300 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Wang, S. I., Parsons, R. & Ittmann, M. Homozygous deletion of the PTEN tumor suppressor gene in a subset of prostate adenocarcinomas. Clin. Cancer Res. 4, 811–815 (1998).

    CAS  PubMed  Google Scholar 

  152. Feilotter, H. E. et al. Analysis of the 10q23 chromosomal region and the PTEN gene in human sporadic breast carcinoma. Br. J. Cancer 79, 718–723 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Freihoff, D. et al. Exclusion of a major role for the PTEN tumour-suppressor gene in breast carcinomas. Br. J. Cancer 79, 754–758 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Pollock, P. M. et al. PTEN inactivation is rare in melanoma tumours but occurs frequently in melanoma cell lines. Melanoma Res. 12, 565–575 (2002).

    Article  CAS  PubMed  Google Scholar 

  155. Birck, A., Ahrenkiel, V., Zeuthen, J., Hou-Jensen, K. & Guldberg, P. Mutation and allelic loss of the PTEN/MMAC1 gene in primary and metastatic melanoma biopsies. J. Invest. Dermatol. 114, 277–280 (2000).

    Article  CAS  PubMed  Google Scholar 

  156. Celebi, J. T., Shendrik, I., Silvers, D. N. & Peacocke, M. Identification of PTEN mutations in metastatic melanoma specimens. J. Med. Genet. 37, 653–657 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Reifenberger, J. et al. Allelic losses on chromosome arm 10q and mutation of the PTEN (MMAC1) tumour suppressor gene in primary and metastatic malignant melanomas. Virchows Arch. 436, 487–493 (2000).

    Article  CAS  PubMed  Google Scholar 

  158. Duerr, E. M. et al. PTEN mutations in gliomas and glioneuronal tumors. Oncogene 16, 2259–2264 (1998).

    Article  CAS  PubMed  Google Scholar 

  159. Rasheed, B. K. et al. PTEN gene mutations are seen in high-grade but not in low-grade gliomas. Cancer Res. 57, 4187–4190 (1997).

    CAS  PubMed  Google Scholar 

  160. Liu, W., James, C. D., Frederick, L., Alderete, B. E. & Jenkins, R. B. PTEN/MMAC1 mutations and EGFR amplification in glioblastomas. Cancer Res. 57, 5254–5257 (1997).

    CAS  PubMed  Google Scholar 

  161. Whang, Y. E. et al. Inactivation of the tumor suppressor PTEN/MMAC1 in advanced human prostate cancer through loss of expression. Proc. Natl Acad. Sci. USA 95, 5246–5250 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Tsao, H., Zhang, X., Benoit, E. & Haluska, F. G. Identification of PTEN/MMAC1 alterations in uncultured melanomas and melanoma cell lines. Oncogene 16, 3397–3402 (1998).

    Article  CAS  PubMed  Google Scholar 

  163. Cheng, J. Q. et al. AKT2, a putative oncogene encoding a member of a subfamily of protein-serine/threonine kinases, is amplified in human ovarian carcinomas. Proc. Natl Acad. Sci. USA 89, 9267–9271 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Staal, S. P. Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: amplification of AKT1 in a primary human gastric adenocarcinoma. Proc. Natl Acad. Sci. USA 84, 5034–5037 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Philp, A. J. et al. The phosphatidylinositol 3′-kinase p85α gene is an oncogene in human ovarian and colon tumors. Cancer Res. 61, 7426–7429 (2001).

    CAS  PubMed  Google Scholar 

  166. Taniguchi, C. M. et al. Phosphoinositide 3-kinase regulatory subunit p85a suppresses insulin action via positive regulation of PTEN. Proc. Natl Acad. Sci. USA (in the press).

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Acknowledgements

We are grateful to members of the Cantley, Soltoff and Carpenter laboratories for thoughtful discussions and insights regarding PI3K signalling. We apologize to the many authors whose work we could not cite directly because of space limitations. Work in the Cantley laboratory is supported by the US National Institutes of Health.

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DATABASES

OMIM

breast cancers

cervical cancers

Cowden disease

gastric cancers

lung cancers

macrocephaly, multiple lipomas and haemangiomata

non-insulin-dependent diabetes mellitus

Peutz–Jegher syndrome

prostate cancers

tuberous sclerosis

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Engelman, J., Luo, J. & Cantley, L. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 7, 606–619 (2006). https://doi.org/10.1038/nrg1879

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