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AKT Signaling in Physiology and Disease

  • Krishna M. Vasudevan
  • Levi A. Garraway
Chapter
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 347)

Abstract

The serine/threonine kinase AKT functions as a critical mediator of signaling downstream of PI3 kinase. Studies over the last two decades have firmly established the importance of AKT in the regulation of cell survival, proliferation, and insulin-dependent metabolic cell responses. AKT executes these diverse tasks through phosphorylation of numerous cellular substrates. Substantial progress has been made in understanding the regulation of AKT activity by upstream kinases and elucidating downstream mechanisms that mediate its myriad cellular effects. Here, we present an overview of AKT regulation and function in physiological and pathological settings. An emphasis is placed on the involvement of aberrant AKT signaling in human diseases ranging from diabetes to cancer and neurological diseases.

Keywords

Vascular Endothelial Growth Factor PI3K Signaling GLUT4 Translocation Hydrophobic Motif Human Epithelial Breast Cancer Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Aguirre V, Werner ED, Giraud J, Lee YH, Shoelson SE, White MF (2002) Phosphorylation of Ser307 in insulin receptor substrate-1 blocks interactions with the insulin receptor and inhibits insulin action. J Biol Chem 277:1531–1537PubMedGoogle Scholar
  2. Ahn JY, Liu X, Liu Z, Pereira L, Cheng D, Peng J, Wade PA, Hamburger AW, Ye K (2006) Nuclear Akt associates with PKC-phosphorylated Ebp1, preventing DNA fragmentation by inhibition of caspase-activated DNase. EMBO J 25:2083–2095PubMedGoogle Scholar
  3. Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P, Hemmings BA (1996) Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J 15:6541–6551PubMedGoogle Scholar
  4. Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB, Cohen P (1997) Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol 7:261–269PubMedGoogle Scholar
  5. Alonso L, Okada H, Pasolli HA, Wakeham A, You-Ten AI, Mak TW, Fuchs E (2005) Sgk3 links growth factor signaling to maintenance of progenitor cells in the hair follicle. J Cell Biol 170:559–570PubMedGoogle Scholar
  6. Altomare DA, Testa JR (2005) Perturbations of the AKT signaling pathway in human cancer. Oncogene 24:7455–7464PubMedGoogle Scholar
  7. Aman MJ, Lamkin TD, Okada H, Kurosaki T, Ravichandran KS (1998) The inositol phosphatase SHIP inhibits Akt/PKB activation in B cells. J Biol Chem 273:33922–33928PubMedGoogle Scholar
  8. Anderson KE, Coadwell J, Stephens LR, Hawkins PT (1998) Translocation of PDK-1 to the plasma membrane is important in allowing PDK-1 to activate protein kinase B. Curr Biol 8:684–691PubMedGoogle Scholar
  9. Arboleda MJ, Lyons JF, Kabbinavar FF, Bray MR, Snow BE, Ayala R, Danino M, Karlan BY, Slamon DJ (2003) Overexpression of AKT2/protein kinase Bbeta leads to up-regulation of beta1 integrins, increased invasion, and metastasis of human breast and ovarian cancer cells. Cancer Res 63:196–206PubMedGoogle Scholar
  10. Barthel A, Okino ST, Liao J, Nakatani K, Li J, Whitlock JP Jr, Roth RA (1999) Regulation of GLUT1 gene transcription by the serine/threonine kinase Akt1. J Biol Chem 274:20281–20286PubMedGoogle Scholar
  11. Bellacosa A, Testa JR, Staal SP, Tsichlis PN (1991) A retroviral oncogene, akt, encoding a serine-threonine kinase containing an SH2-like region. Science 254:274–277PubMedGoogle Scholar
  12. Bellacosa A, Testa JR, Moore R, Larue L (2004) A portrait of AKT kinases: human cancer and animal models depict a family with strong individualities. Cancer Biol Ther 3:268–275PubMedGoogle Scholar
  13. Bellacosa A, Kumar CC, Di Cristofano A, Testa JR (2005) Activation of AKT kinases in cancer: implications for therapeutic targeting. Adv Cancer Res 94:29–86PubMedGoogle Scholar
  14. Bhaskar PT, Hay N (2007) The two TORCs and Akt. Dev Cell 12:487–502PubMedGoogle Scholar
  15. Bjornsti MA, Houghton PJ (2004) The TOR pathway: a target for cancer therapy. Nat Rev Cancer 4:335–348PubMedGoogle Scholar
  16. Boehme KA, Kulikov R, Blattner C (2008) p53 stabilization in response to DNA damage requires Akt/PKB and DNA-PK. Proc Natl Acad Sci USA 105:7785–7790PubMedGoogle Scholar
  17. Bozulic L, Hemmings BA (2009) PIKKing on PKB: regulation of PKB activity by phosphorylation. Curr Opin Cell Biol 21:256–261PubMedGoogle Scholar
  18. Bozulic L, Surucu B, Hynx D, Hemmings BA (2008) PKBalpha/Akt1 acts downstream of DNA-PK in the DNA double-strand break response and promotes survival. Mol Cell 30:203–213PubMedGoogle Scholar
  19. Brazil DP, Park J, Hemmings BA (2002) PKB binding proteins. Getting in on the Akt. Cell 111:293–303PubMedGoogle Scholar
  20. Brognard J, Newton AC (2008) PHLiPPing the switch on Akt and protein kinase C signaling. Trends Endocrinol Metab 19:223–230PubMedGoogle Scholar
  21. Brognard J, Sierecki E, Gao T, Newton AC (2007) PHLPP and a second isoform, PHLPP2, differentially attenuate the amplitude of Akt signaling by regulating distinct Akt isoforms. Mol Cell 25:917–931PubMedGoogle Scholar
  22. Burke RE (2007) Inhibition of mitogen-activated protein kinase and stimulation of Akt kinase signaling pathways: Two approaches with therapeutic potential in the treatment of neurodegenerative disease. Pharmacol Ther 114:261–277PubMedGoogle Scholar
  23. Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296:1655–1657PubMedGoogle Scholar
  24. Cantley LC, Neel BG (1999) New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci USA 96:4240–4245PubMedGoogle Scholar
  25. Cantrell D (2002) Protein kinase B (Akt) regulation and function in T lymphocytes. Semin Immunol 14:19–26PubMedGoogle Scholar
  26. Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, Frisch S, Reed JC (1998) Regulation of cell death protease caspase-9 by phosphorylation. Science 282:1318–1321PubMedGoogle Scholar
  27. Carpten JD, Faber AL, Horn C, Donoho GP, Briggs SL, Robbins CM, Hostetter G, Boguslawski S, Moses TY, Savage S, Uhlik M, Lin A, Du J, Qian YW, Zeckner DJ, Tucker-Kellogg G, Touchman J, Patel K, Mousses S, Bittner M, Schevitz R, Lai MH, Blanchard KL, Thomas JE (2007) A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 448:439–444PubMedGoogle Scholar
  28. Cha TL, Zhou BP, Xia W, Wu Y, Yang CC, Chen CT, Ping B, Otte AP, Hung MC (2005) Akt-mediated phosphorylation of EZH2 suppresses methylation of lysine 27 in histone H3. Science 310:306–310PubMedGoogle Scholar
  29. Chen R, Kim O, Yang J, Sato K, Eisenmann KM, McCarthy J, Chen H, Qiu Y (2001) Regulation of Akt/PKB activation by tyrosine phosphorylation. J Biol Chem 276:31858–31862PubMedGoogle Scholar
  30. Chen HK, Fernandez-Funez P, Acevedo SF, Lam YC, Kaytor MD, Fernandez MH, Aitken A, Skoulakis EM, Orr HT, Botas J, Zoghbi HY (2003) Interaction of Akt-phosphorylated ataxin-1 with 14-3-3 mediates neurodegeneration in spinocerebellar ataxia type 1. Cell 113:457–468PubMedGoogle Scholar
  31. Chen J, Somanath PR, Razorenova O, Chen WS, Hay N, Bornstein P, Byzova TV (2005a) Akt1 regulates pathological angiogenesis, vascular maturation and permeability in vivo. Nat Med 11:1188–1196PubMedGoogle Scholar
  32. Chen Z, Trotman LC, Shaffer D, Lin HK, Dotan ZA, Niki M, Koutcher JA, Scher HI, Ludwig T, Gerald W, Cordon-Cardo C, Pandolfi PP (2005b) Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature 436:725–730PubMedGoogle Scholar
  33. Chen ML, Xu PZ, Peng XD, Chen WS, Guzman G, Yang X, Di Cristofano A, Pandolfi PP, Hay N (2006) The deficiency of Akt1 is sufficient to suppress tumor development in Pten+/− mice. Genes Dev 20:1569–1574PubMedGoogle Scholar
  34. Cho H, Mu J, Kim JK, Thorvaldsen JL, Chu Q, Crenshaw EB III, Kaestner KH, Bartolomei MS, Shulman GI, Birnbaum MJ (2001) Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta). Science 292:1728–1731PubMedGoogle Scholar
  35. Coffer PJ, Woodgett JR (1991) Molecular cloning and characterisation of a novel putative protein-serine kinase related to the cAMP-dependent and protein kinase C families. Eur J Biochem 201:475–481PubMedGoogle Scholar
  36. Colin E, Regulier E, Perrin V, Durr A, Brice A, Aebischer P, Deglon N, Humbert S, Saudou F (2005) Akt is altered in an animal model of Huntington's disease and in patients. Eur J Neurosci 21:1478–1488PubMedGoogle Scholar
  37. Dai B, Kim O, Xie Y, Guo Z, Xu K, Wang B, Kong X, Melamed J, Chen H, Bieberich CJ, Borowsky AD, Kung HJ, Wei G, Ostrowski MC, Brodie A, Qiu Y (2006) Tyrosine kinase Etk/BMX is up-regulated in human prostate cancer and its overexpression induces prostate intraepithelial neoplasia in mouse. Cancer Res 66:8058–8064PubMedGoogle Scholar
  38. Davies MA, Stemke-Hale K, Tellez C, Calderone TL, Deng W, Prieto VG, Lazar AJ, Gershenwald JE, Mills GB (2008) A novel AKT3 mutation in melanoma tumours and cell lines. Br J Cancer 99:1265–1268PubMedGoogle Scholar
  39. Di Cristofano A, Kotsi P, Peng YF, Cordon-Cardo C, Elkon KB, Pandolfi PP (1999) Impaired Fas response and autoimmunity in Pten+/− mice. Science 285:2122–2125PubMedGoogle Scholar
  40. Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM (1999) Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature 399:601–605PubMedGoogle Scholar
  41. Du K, Herzig S, Kulkarni RN, Montminy M (2003) TRB3: a tribbles homolog that inhibits Akt/PKB activation by insulin in liver. Science 300:1574–1577PubMedGoogle Scholar
  42. Dummler B, Hemmings BA (2007) Physiological roles of PKB/Akt isoforms in development and disease. Biochem Soc Trans 35:231–235PubMedGoogle Scholar
  43. Dummler B, Tschopp O, Hynx D, Yang ZZ, Dirnhofer S, Hemmings BA (2006) Life with a single isoform of Akt: mice lacking Akt2 and Akt3 are viable but display impaired glucose homeostasis and growth deficiencies. Mol Cell Biol 26:8042–8051PubMedGoogle Scholar
  44. Easton RM, Cho H, Roovers K, Shineman DW, Mizrahi M, Forman MS, Lee VM, Szabolcs M, de Jong R, Oltersdorf T, Ludwig T, Efstratiadis A, Birnbaum MJ (2005) Role for Akt3/protein kinase Bgamma in attainment of normal brain size. Mol Cell Biol 25:1869–1878PubMedGoogle Scholar
  45. Elghazi L, Rachdi L, Weiss AJ, Cras-Meneur C, Bernal-Mizrachi E (2007) Regulation of beta-cell mass and function by the Akt/protein kinase B signalling pathway. Diabetes Obes Metab 9(Suppl 2):147–157PubMedGoogle Scholar
  46. Engelman JA, Luo J, Cantley LC (2006) The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 7:606–619PubMedGoogle Scholar
  47. Enomoto A, Murakami H, Asai N, Morone N, Watanabe T, Kawai K, Murakumo Y, Usukura J, Kaibuchi K, Takahashi M (2005) Akt/PKB regulates actin organization and cell motility via Girdin/APE. Dev Cell 9:389–402PubMedGoogle Scholar
  48. Feng J, Park J, Cron P, Hess D, Hemmings BA (2004) Identification of a PKB/Akt hydrophobic motif Ser-473 kinase as DNA-dependent protein kinase. J Biol Chem 279:41189–41196PubMedGoogle Scholar
  49. Franke TF, Kaplan DR, Cantley LC, Toker A (1997) Direct regulation of the Akt proto-oncogene product by phosphatidylinositol-3, 4-bisphosphate. Science 275:665–668PubMedGoogle Scholar
  50. Fruman DA (2004) Phosphoinositide 3-kinase and its targets in B-cell and T-cell signaling. Curr Opin Immunol 16:314–320PubMedGoogle Scholar
  51. Fulton D, Gratton JP, McCabe TJ, Fontana J, Fujio Y, Walsh K, Franke TF, Papapetropoulos A, Sessa WC (1999) Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 399:597–601PubMedGoogle Scholar
  52. Gao T, Furnari F, Newton AC (2005) PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth. Mol Cell 18:13–24PubMedGoogle Scholar
  53. George S, Rochford JJ, Wolfrum C, Gray SL, Schinner S, Wilson JC, Soos MA, Murgatroyd PR, Williams RM, Acerini CL, Dunger DB, Barford D, Umpleby AM, Wareham NJ, Davies HA, Schafer AJ, Stoffel M, O'Rahilly S, Barroso I (2004) A family with severe insulin resistance and diabetes due to a mutation in AKT2. Science 304:1325–1328PubMedGoogle Scholar
  54. Georgescu MM, Kirsch KH, Akagi T, Shishido T, Hanafusa H (1999) The tumor-suppressor activity of PTEN is regulated by its carboxyl-terminal region. Proc Natl Acad Sci USA 96:10182–10187PubMedGoogle Scholar
  55. Gordan JD, Simon MC (2007) Hypoxia-inducible factors: central regulators of the tumor phenotype. Curr Opin Genet Dev 17:71–77PubMedGoogle Scholar
  56. Goswami A, Ranganathan P, Rangnekar VM (2006) The phosphoinositide 3-kinase/Akt1/Par-4 axis: a cancer-selective therapeutic target. Cancer Res 66:2889–2892PubMedGoogle Scholar
  57. Gottlob K, Majewski N, Kennedy S, Kandel E, Robey RB, Hay N (2001) Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase. Genes Dev 15:1406–1418PubMedGoogle Scholar
  58. Habib T, Hejna JA, Moses RE, Decker SJ (1998) Growth factors and insulin stimulate tyrosine phosphorylation of the 51C/SHIP2 protein. J Biol Chem 273:18605–18609PubMedGoogle Scholar
  59. Haruta T, Uno T, Kawahara J, Takano A, Egawa K, Sharma PM, Olefsky JM, Kobayashi M (2000) A rapamycin-sensitive pathway down-regulates insulin signaling via phosphorylation and proteasomal degradation of insulin receptor substrate-1. Mol Endocrinol 14:783–794PubMedGoogle Scholar
  60. Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB (2005) Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov 4:988–1004PubMedGoogle Scholar
  61. Humbert S, Bryson EA, Cordelieres FP, Connors NC, Datta SR, Finkbeiner S, Greenberg ME, Saudou F (2002) The IGF-1/Akt pathway is neuroprotective in Huntington's disease and involves Huntingtin phosphorylation by Akt. Dev Cell 2:831–837PubMedGoogle Scholar
  62. Hutchinson JN, Jin J, Cardiff RD, Woodgett JR, Muller WJ (2004) Activation of Akt-1 (PKB-alpha) can accelerate ErbB-2-mediated mammary tumorigenesis but suppresses tumor invasion. Cancer Res 64:3171–3178PubMedGoogle Scholar
  63. Ikenoue T, Kanai F, Hikiba Y, Obata T, Tanaka Y, Imamura J, Ohta M, Jazag A, Guleng B, Tateishi K, Asaoka Y, Matsumura M, Kawabe T, Omata M (2005) Functional analysis of PIK3CA gene mutations in human colorectal cancer. Cancer Res 65:4562–4567PubMedGoogle Scholar
  64. Irie HY, Pearline RV, Grueneberg D, Hsia M, Ravichandran P, Kothari N, Natesan S, Brugge JS (2005) Distinct roles of Akt1 and Akt2 in regulating cell migration and epithelial-mesenchymal transition. J Cell Biol 171:1023–1034PubMedGoogle Scholar
  65. Isakoff SJ, Cardozo T, Andreev J, Li Z, Ferguson KM, Abagyan R, Lemmon MA, Aronheim A, Skolnik EY (1998) Identification and analysis of PH domain-containing targets of phosphatidylinositol 3-kinase using a novel in vivo assay in yeast. EMBO J 17:5374–5387PubMedGoogle Scholar
  66. Ishihara H, Sasaoka T, Hori H, Wada T, Hirai H, Haruta T, Langlois WJ, Kobayashi M (1999) Molecular cloning of rat SH2-containing inositol phosphatase 2 (SHIP2) and its role in the regulation of insulin signaling. Biochem Biophys Res Commun 260:265–272PubMedGoogle Scholar
  67. Jiang T, Qiu Y (2003) Interaction between Src and a C-terminal proline-rich motif of Akt is required for Akt activation. J Biol Chem 278:15789–15793PubMedGoogle Scholar
  68. Jiang BH, Zheng JZ, Aoki M, Vogt PK (2000) Phosphatidylinositol 3-kinase signaling mediates angiogenesis and expression of vascular endothelial growth factor in endothelial cells. Proc Natl Acad Sci USA 97:1749–1753PubMedGoogle Scholar
  69. Jones PF, Jakubowicz T, Pitossi FJ, Maurer F, Hemmings BA (1991) Molecular cloning and identification of a serine/threonine protein kinase of the second-messenger subfamily. Proc Natl Acad Sci USA 88:4171–4175PubMedGoogle Scholar
  70. Jones RG, Parsons M, Bonnard M, Chan VS, Yeh WC, Woodgett JR, Ohashi PS (2000) Protein kinase B regulates T lymphocyte survival, nuclear factor kappaB activation, and Bcl-X(L) levels in vivo. J Exp Med 191:1721–1734PubMedGoogle Scholar
  71. Kandel ES, Hay N (1999) The regulation and activities of the multifunctional serine/threonine kinase Akt/PKB. Exp Cell Res 253:210–229PubMedGoogle Scholar
  72. Kane LP, Andres PG, Howland KC, Abbas AK, Weiss A (2001) Akt provides the CD28 costimulatory signal for up-regulation of IL-2 and IFN-gamma but not TH2 cytokines. Nat Immunol 2:37–44PubMedGoogle Scholar
  73. Kaneto H, Matsuoka TA, Nakatani Y, Kawamori D, Miyatsuka T, Matsuhisa M, Yamasaki Y (2005) Oxidative stress, ER stress, and the JNK pathway in type 2 diabetes. J Mol Med 83:429–439PubMedGoogle Scholar
  74. Kang SS, Kwon T, Kwon DY, Do SI (1999) Akt protein kinase enhances human telomerase activity through phosphorylation of telomerase reverse transcriptase subunit. J Biol Chem 274:13085–13090PubMedGoogle Scholar
  75. Kang S, Bader AG, Vogt PK (2005) Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc Natl Acad Sci USA 102:802–807PubMedGoogle Scholar
  76. Karlsson HK, Hallsten K, Bjornholm M, Tsuchida H, Chibalin AV, Virtanen KA, Heinonen OJ, Lonnqvist F, Nuutila P, Zierath JR (2005) Effects of metformin and rosiglitazone treatment on insulin signaling and glucose uptake in patients with newly diagnosed type 2 diabetes: a randomized controlled study. Diabetes 54:1459–1467PubMedGoogle Scholar
  77. Kawase T, Ohki R, Shibata T, Tsutsumi S, Kamimura N, Inazawa J, Ohta T, Ichikawa H, Aburatani H, Tashiro F, Taya Y (2009) PH domain-only protein PHLDA3 is a p53-regulated repressor of Akt. Cell 136:535–550PubMedGoogle Scholar
  78. Kitamura T, Asai N, Enomoto A, Maeda K, Kato T, Ishida M, Jiang P, Watanabe T, Usukura J, Kondo T, Costantini F, Murohara T, Takahashi M (2008) Regulation of VEGF-mediated angiogenesis by the Akt/PKB substrate Girdin. Nat Cell Biol 10:329–337PubMedGoogle Scholar
  79. Kovacina KS, Park GY, Bae SS, Guzzetta AW, Schaefer E, Birnbaum MJ, Roth RA (2003) Identification of a proline-rich Akt substrate as a 14-3-3 binding partner. J Biol Chem 278:10189–10194PubMedGoogle Scholar
  80. Lemmon MA (2003) Phosphoinositide recognition domains. Traffic 4:201–213PubMedGoogle Scholar
  81. Li X, Monks B, Ge Q, Birnbaum MJ (2007) Akt/PKB regulates hepatic metabolism by directly inhibiting PGC-1alpha transcription coactivator. Nature 447:1012–1016PubMedGoogle Scholar
  82. Liaw D, Marsh DJ, Li J, Dahia PL, Wang SI, Zheng Z, Bose S, Call KM, Tsou HC, Peacocke M, Eng C, Parsons R (1997) Germline mutations of the PTEN gene in Cowden disease, an inherited breast and thyroid cancer syndrome. Nat Genet 16:64–67PubMedGoogle Scholar
  83. Liu Q, Sasaki T, Kozieradzki I, Wakeham A, Itie A, Dumont DJ, Penninger JM (1999) SHIP is a negative regulator of growth factor receptor-mediated PKB/Akt activation and myeloid cell survival. Genes Dev 13:786–791PubMedGoogle Scholar
  84. Liu H, Radisky DC, Nelson CM, Zhang H, Fata JE, Roth RA, Bissell MJ (2006) Mechanism of Akt1 inhibition of breast cancer cell invasion reveals a protumorigenic role for TSC2. Proc Natl Acad Sci USA 103:4134–4139PubMedGoogle Scholar
  85. Maddika S, Panigrahi S, Wiechec E, Wesselborg S, Fischer U, Schulze-Osthoff K, Los M (2009) Unscheduled Akt-triggered activation of cyclin-dependent kinase 2 as a key effector mechanism of apoptin's anticancer toxicity. Mol Cell Biol 29:1235–1248PubMedGoogle Scholar
  86. Maira SM, Galetic I, Brazil DP, Kaech S, Ingley E, Thelen M, Hemmings BA (2001) Carboxyl-terminal modulator protein (CTMP), a negative regulator of PKB/Akt and v-Akt at the plasma membrane. Science 294:374–380PubMedGoogle Scholar
  87. Majumder PK, Yeh JJ, George DJ, Febbo PG, Kum J, Xue Q, Bikoff R, Ma H, Kantoff PW, Golub TR, Loda M, Sellers WR (2003) Prostate intraepithelial neoplasia induced by prostate restricted Akt activation: the MPAKT model. Proc Natl Acad Sci USA 100:7841–7846PubMedGoogle Scholar
  88. Majumder PK, Febbo PG, Bikoff R, Berger R, Xue Q, McMahon LM, Manola J, Brugarolas J, McDonnell TJ, Golub TR, Loda M, Lane HA, Sellers WR (2004) mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med 10:594–601PubMedGoogle Scholar
  89. Manning BD, Cantley LC (2007) AKT/PKB signaling: navigating downstream. Cell 129:1261–1274PubMedGoogle Scholar
  90. Marsh DJ, Dahia PL, Zheng Z, Liaw D, Parsons R, Gorlin RJ, Eng C (1997) Germline mutations in PTEN are present in Bannayan-Zonana syndrome. Nat Genet 16:333–334PubMedGoogle Scholar
  91. Mayo LD, Donner DB (2001) A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus. Proc Natl Acad Sci USA 98:11598–11603PubMedGoogle Scholar
  92. McCormick JA, Feng Y, Dawson K, Behne MJ, Yu B, Wang J, Wyatt AW, Henke G, Grahammer F, Mauro TM, Lang F, Pearce D (2004) Targeted disruption of the protein kinase SGK3/CISK impairs postnatal hair follicle development. Mol Biol Cell 15:4278–4288PubMedGoogle Scholar
  93. Mohamed AJ, Yu L, Backesjo CM, Vargas L, Faryal R, Aints A, Christensson B, Berglof A, Vihinen M, Nore BF, Smith CI (2009) Bruton's tyrosine kinase (Btk): function, regulation, and transformation with special emphasis on the PH domain. Immunol Rev 228:58–73PubMedGoogle Scholar
  94. Muise-Helmericks RC, Grimes HL, Bellacosa A, Malstrom SE, Tsichlis PN, Rosen N (1998) Cyclin D expression is controlled post-transcriptionally via a phosphatidylinositol 3-kinase/Akt-dependent pathway. J Biol Chem 273:29864–29872PubMedGoogle Scholar
  95. Nogueira V, Park Y, Chen CC, Xu PZ, Chen ML, Tonic I, Unterman T, Hay N (2008) Akt determines replicative senescence and oxidative or oncogenic premature senescence and sensitizes cells to oxidative apoptosis. Cancer Cell 14:458–470PubMedGoogle Scholar
  96. O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, Lane H, Hofmann F, Hicklin DJ, Ludwig DL, Baselga J, Rosen N (2006) mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 66:1500–1508PubMedGoogle Scholar
  97. Padmanabhan S, Mukhopadhyay A, Narasimhan SD, Tesz G, Czech MP, Tissenbaum HA (2009) A PP2A regulatory subunit regulates C. elegans insulin/IGF-1 signaling by modulating AKT-1 phosphorylation. Cell 136:939–951PubMedGoogle Scholar
  98. Park BK, Zeng X, Glazer RI (2001) Akt1 induces extracellular matrix invasion and matrix metalloproteinase-2 activity in mouse mammary epithelial cells. Cancer Res 61:7647–7653PubMedGoogle Scholar
  99. Park J, Feng J, Li Y, Hammarsten O, Brazil DP, Hemmings BA (2009) DNA-dependent protein kinase-mediated phosphorylation of protein kinase B requires a specific recognition sequence in the C-terminal hydrophobic motif. J Biol Chem 284:6169–6174PubMedGoogle Scholar
  100. Pedersen O (1999) Genetics of insulin resistance. Exp Clin Endocrinol Diabetes 107:113–118PubMedGoogle Scholar
  101. Philp AJ, Campbell IG, Leet C, Vincan E, Rockman SP, Whitehead RH, Thomas RJ, Phillips WA (2001) The phosphatidylinositol 3'-kinase p85alpha gene is an oncogene in human ovarian and colon tumors. Cancer Res 61:7426–7429PubMedGoogle Scholar
  102. Podsypanina K, Ellenson LH, Nemes A, Gu J, Tamura M, Yamada KM, Cordon-Cardo C, Catoretti G, Fisher PE, Parsons R (1999) Mutation of Pten/Mmac1 in mice causes neoplasia in multiple organ systems. Proc Natl Acad Sci USA 96:1563–1568PubMedGoogle Scholar
  103. Prudente S, Hribal ML, Flex E, Turchi F, Morini E, De Cosmo S, Bacci S, Tassi V, Cardellini M, Lauro R, Sesti G, Dallapiccola B, Trischitta V (2005) The functional Q84R polymorphism of mammalian Tribbles homolog TRB3 is associated with insulin resistance and related cardiovascular risk in Caucasians from Italy. Diabetes 54:2807–2811PubMedGoogle Scholar
  104. Qiu Y, Robinson D, Pretlow TG, Kung HJ (1998) Etk/Bmx, a tyrosine kinase with a pleckstrin-homology domain, is an effector of phosphatidylinositol 3'-kinase and is involved in interleukin 6-induced neuroendocrine differentiation of prostate cancer cells. Proc Natl Acad Sci USA 95:3644–3649PubMedGoogle Scholar
  105. Rangone H, Pardo R, Colin E, Girault JA, Saudou F, Humbert S (2005) Phosphorylation of arfaptin 2 at Ser260 by Akt Inhibits PolyQ-huntingtin-induced toxicity by rescuing proteasome impairment. J Biol Chem 280:22021–22028PubMedGoogle Scholar
  106. Rathmell JC, Elstrom RL, Cinalli RM, Thompson CB (2003) Activated Akt promotes increased resting T cell size, CD28-independent T cell growth, and development of autoimmunity and lymphoma. Eur J Immunol 33:2223–2232PubMedGoogle Scholar
  107. Read DE, Gorman AM (2009) Involvement of Akt in neurite outgrowth. Cell Mol Life Sci 66:2975–2984PubMedGoogle Scholar
  108. Ruggero D, Pandolfi PP (2003) Does the ribosome translate cancer? Nat Rev Cancer 3:179–192PubMedGoogle Scholar
  109. Samuels Y, Ericson K (2006) Oncogenic PI3K and its role in cancer. Curr Opin Oncol 18:77–82PubMedGoogle Scholar
  110. Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ, Willson JK, Markowitz S, Kinzler KW, Vogelstein B, Velculescu VE (2004) High frequency of mutations of the PIK3CA gene in human cancers. Science 304:554PubMedGoogle Scholar
  111. Samuels Y, Diaz LA Jr, Schmidt-Kittler O, Cummins JM, Delong L, Cheong I, Rago C, Huso DL, Lengauer C, Kinzler KW, Vogelstein B, Velculescu VE (2005) Mutant PIK3CA promotes cell growth and invasion of human cancer cells. Cancer Cell 7:561–573PubMedGoogle Scholar
  112. Sansal I, Sellers WR (2004) The biology and clinical relevance of the PTEN tumor suppressor pathway. J Clin Oncol 22:2954–2963PubMedGoogle Scholar
  113. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM (2005) Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 307:1098–1101PubMedGoogle Scholar
  114. Sato S, Fujita N, Tsuruo T (2000) Modulation of Akt kinase activity by binding to Hsp90. Proc Natl Acad Sci USA 97:10832–10837PubMedGoogle Scholar
  115. Scheid MP, Woodgett JR (2001) PKB/AKT: functional insights from genetic models. Nat Rev Mol Cell Biol 2:760–768PubMedGoogle Scholar
  116. Shah OJ, Hunter T (2004) Critical role of T-loop and H-motif phosphorylation in the regulation of S6 kinase 1 by the tuberous sclerosis complex. J Biol Chem 279:20816–20823PubMedGoogle Scholar
  117. Shao Z, Bhattacharya K, Hsich E, Park L, Walters B, Germann U, Wang YM, Kyriakis J, Mohanlal R, Kuida K, Namchuk M, Salituro F, Yao YM, Hou WM, Chen X, Aronovitz M, Tsichlis PN, Bhattacharya S, Force T, Kilter H (2006) c-Jun N-terminal kinases mediate reactivation of Akt and cardiomyocyte survival after hypoxic injury in vitro and in vivo. Circ Res 98:111–118PubMedGoogle Scholar
  118. Shiojima I, Sato K, Izumiya Y, Schiekofer S, Ito M, Liao R, Colucci WS, Walsh K (2005) Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure. J Clin Invest 115:2108–2118PubMedGoogle Scholar
  119. Shoji K, Oda K, Nakagawa S, Hosokawa S, Nagae G, Uehara Y, Sone K, Miyamoto Y, Hiraike H, Hiraike-Wada O, Nei T, Kawana K, Kuramoto H, Aburatani H, Yano T, Taketani Y (2009) The oncogenic mutation in the pleckstrin homology domain of AKT1 in endometrial carcinomas. Br J Cancer 101:145–148PubMedGoogle Scholar
  120. Staal SP, Hartley JW, Rowe WP (1977) Isolation of transforming murine leukemia viruses from mice with a high incidence of spontaneous lymphoma. Proc Natl Acad Sci USA 74:3065–3067PubMedGoogle Scholar
  121. Stephens L, Anderson K, Stokoe D, Erdjument-Bromage H, Painter GF, Holmes AB, Gaffney PR, Reese CB, McCormick F, Tempst P, Coadwell J, Hawkins PT (1998) Protein kinase B kinases that mediate phosphatidylinositol 3, 4, 5-trisphosphate-dependent activation of protein kinase B. Science 279:710–714PubMedGoogle Scholar
  122. Stokoe D, Stephens LR, Copeland T, Gaffney PR, Reese CB, Painter GF, Holmes AB, McCormick F, Hawkins PT (1997) Dual role of phosphatidylinositol-3, 4, 5-trisphosphate in the activation of protein kinase B. Science 277:567–570PubMedGoogle Scholar
  123. Suzuki A, de la Pompa JL, Stambolic V, Elia AJ, Sasaki T, del Barco Barrantes I, Ho A, Wakeham A, Itie A, Khoo W, Fukumoto M, Mak TW (1998) High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Curr Biol 8:1169–1178PubMedGoogle Scholar
  124. Taha C, Liu Z, Jin J, Al-Hasani H, Sonenberg N, Klip A (1999) Opposite translational control of GLUT1 and GLUT4 glucose transporter mRNAs in response to insulin. Role of mammalian target of rapamycin, protein kinase b, and phosphatidylinositol 3-kinase in GLUT1 mRNA translation. J Biol Chem 274:33085–33091PubMedGoogle Scholar
  125. Tessier M, Woodgett JR (2006) Serum and glucocorticoid-regulated protein kinases: variations on a theme. J Cell Biochem 98:1391–1407PubMedGoogle Scholar
  126. Um SH, Frigerio F, Watanabe M, Picard F, Joaquin M, Sticker M, Fumagalli S, Allegrini PR, Kozma SC, Auwerx J, Thomas G (2004) Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature 431:200–205PubMedGoogle Scholar
  127. Vanhaesebroeck B, Alessi DR (2000) The PI3K-PDK1 connection: more than just a road to PKB. Biochem J 346(Pt 3):561–576PubMedGoogle Scholar
  128. Vasudevan KM, Gurumurthy S, Rangnekar VM (2004) Suppression of PTEN expression by NF-kappa B prevents apoptosis. Mol Cell Biol 24:1007–1021PubMedGoogle Scholar
  129. Vasudevan KM, Burikhanov R, Goswami A, Rangnekar VM (2007) Suppression of PTEN expression is essential for antiapoptosis and cellular transformation by oncogenic Ras. Cancer Res 67:10343–10350PubMedGoogle Scholar
  130. Vasudevan KM, Barbie DA, Davies MA, Rabinovsky R, McNear CJ, Kim JJ, Hennessy BT, Tseng H, Pochanard P, Kim SY, Dunn IF, Schinzel AC, Sandy P, Hoersch S, Sheng Q, Gupta PB, Boehm JS, Reiling JH, Silver S, Lu Y, Stemke-Hale K, Dutta B, Joy C, Sahin AA, Gonzalez-Angulo AM, Lluch A, Rameh LE, Jacks T, Root DE, Lander ES, Mills GB, Hahn WC, Sellers WR, Garraway LA (2009) AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. Cancer Cell 16:21–32PubMedGoogle Scholar
  131. Virbasius JV, Song X, Pomerleau DP, Zhan Y, Zhou GW, Czech MP (2001) Activation of the Akt-related cytokine-independent survival kinase requires interaction of its phox domain with endosomal phosphatidylinositol 3-phosphate. Proc Natl Acad Sci USA 98:12908–12913PubMedGoogle Scholar
  132. Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2:489–501PubMedGoogle Scholar
  133. Vivanco I, Palaskas N, Tran C, Finn SP, Getz G, Kennedy NJ, Jiao J, Rose J, Xie W, Loda M, Golub T, Mellinghoff IK, Davis RJ, Wu H, Sawyers CL (2007) Identification of the JNK signaling pathway as a functional target of the tumor suppressor PTEN. Cancer Cell 11:555–569PubMedGoogle Scholar
  134. Wang Q, Liu L, Pei L, Ju W, Ahmadian G, Lu J, Wang Y, Liu F, Wang YT (2003) Control of synaptic strength, a novel function of Akt. Neuron 38:915–928PubMedGoogle Scholar
  135. Watson RT, Pessin JE (2006) Bridging the GAP between insulin signaling and GLUT4 translocation. Trends Biochem Sci 31:215–222PubMedGoogle Scholar
  136. Yoeli-Lerner M, Yiu GK, Rabinovitz I, Erhardt P, Jauliac S, Toker A (2005) Akt blocks breast cancer cell motility and invasion through the transcription factor NFAT. Mol Cell 20:539–550PubMedGoogle Scholar
  137. Zhou GL, Tucker DF, Bae SS, Bhatheja K, Birnbaum MJ, Field J (2006) Opposing roles for Akt1 and Akt2 in Rac/Pak signaling and cell migration. J Biol Chem 281:36443–36453PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  1. 1.Department of Medical OncologyDana-Farber Cancer Institute, Harvard Medical SchoolBostonUSA
  2. 2.Center for Cancer Genome DiscoveryDana-Farber Cancer Institute, Harvard Medical SchoolBostonUSA
  3. 3.Department of MedicineBrigham and Women’s Hospital, Harvard Medical SchoolBostonUSA
  4. 4.The Broad InstituteCambridgeUSA

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