Phosphoinositide 3-Kinases in Health and Disease

  • Alessandra Ghigo
  • Fulvio Morello
  • Alessia Perino
  • Emilio HirschEmail author
Part of the Subcellular Biochemistry book series (SCBI, volume 58)


In the last decade, the availability of genetically modified animals has revealed interesting roles for phosphoinositide 3-kinases (PI3Ks) as signaling platforms orchestrating multiple cellular responses, both in health and pathology. By acting downstream distinct receptor types, PI3Ks nucleate complex signaling assemblies controlling several biological process, ranging from cell proliferation and survival to immunity, cancer, metabolism and cardiovascular control. While the involvement of these kinases in modulating immune reactions and neoplastic transformation has long been accepted, recent progress from our group and others has highlighted new and unforeseen roles of PI3Ks in controlling cardiovascular function. Hence, the view is emerging that pharmacological targeting of distinct PI3K isoforms could be successful in treating disorders such as myocardial infarction and heart failure, besides inflammatory diseases and cancer. Currently, PI3Ks represent attractive drug targets for companies interested in the development of novel and safe treatments for such diseases. Numerous hit and lead compounds are now becoming available and, for some of them, clinical trials can be envisaged in the near future. In the following sections, we will outline the impact of specific PI3K isoforms in regulating different cellular contexts, including immunity, metabolism, cancer and cardiovascular system, both in physiological and disease conditions.


Cancer Immunity Inflammation Glucose metabolism Heart failure 


  1. Agati JM, Yeagley D, Quinn PG (1998) Assessment of the roles of mitogen-activated protein kinase, phosphatidylinositol 3-kinase, protein kinase B, and protein kinase C in insulin inhibition of cAMP-induced phosphoenolpyruvate carboxykinase gene transcription. J Biol Chem 273:18751–18759CrossRefPubMedGoogle Scholar
  2. Alcazar I, Marques M, Kumar A, Hirsch E, Wymann M, Carrera AC, Barber DF (2007) Phosphoinositide 3-kinase gamma participates in T cell receptor-induced T cell activation. J Exp Med 204:2977–2987CrossRefPubMedGoogle Scholar
  3. Ali K, Bilancio A, Thomas M, Pearce W, Gilfillan AM, Tkaczyk C, Kuehn N, Gray A, Giddings J, Peskett E et al (2004) Essential role for the p110delta phosphoinositide 3-kinase in the allergic response. Nature 431:1007–1011CrossRefPubMedGoogle Scholar
  4. Ali K, Camps M, Pearce WP, Ji H, Ruckle T, Kuehn N, Pasquali C, Chabert C, Rommel C, Vanhaesebroeck B (2008) Isoform-specific functions of phosphoinositide 3-kinases: p110 delta but not p110 gamma promotes optimal allergic responses in vivo. J Immunol 180:2538–2544PubMedGoogle Scholar
  5. Bachman KE, Argani P, Samuels Y, Silliman N, Ptak J, Szabo S, Konishi H, Karakas B, Blair BG, Lin C et al (2004) The PIK3CA gene is mutated with high frequency in human breast cancers. Cancer Biol Ther 3:772–775CrossRefPubMedGoogle Scholar
  6. Bader AG, Kang S, Vogt PK (2006) Cancer-specific mutations in PIK3CA are oncogenic in vivo. Proc Natl Acad Sci USA 103:1475–1479CrossRefPubMedGoogle Scholar
  7. Bai L, Wang Y, Fan J, Chen Y, Ji W, Qu A, Xu P, James DE, Xu T (2007) Dissecting multiple steps of GLUT4 trafficking and identifying the sites of insulin action. Cell Metab 5:47–57CrossRefPubMedGoogle Scholar
  8. Bandyopadhyay GK, Yu JG, Ofrecio J, Olefsky JM (2005) Increased p85/55/50 expression and decreased phosphotidylinositol 3-kinase activity in insulin-resistant human skeletal muscle. Diabetes 54:2351–2359CrossRefPubMedGoogle Scholar
  9. Baraldo S, Lokar Oliani K, Turato G, Zuin R, Saetta M (2007) The role of lymphocytes in the pathogenesis of asthma and COPD. Curr Med Chem 14:2250–2256CrossRefPubMedGoogle Scholar
  10. Barber DF, Bartolome A, Hernandez C, Flores JM, Fernandez-Arias C, Rodriguez-Borlado L, Hirsch E, Wymann M, Balomenos D, Carrera AC (2006) Class IB-phosphatidylinositol 3-kinase (PI3K) deficiency ameliorates IA-PI3K-induced systemic lupus but not T cell invasion. J Immunol 176:589–593PubMedGoogle Scholar
  11. Barberis L, Pasquali C, Bertschy-Meier D, Cuccurullo A, Costa C, Ambrogio C, Vilbois F, Chiarle R, Wymann M, Altruda F et al (2009) Leukocyte transmigration is modulated by chemokine-mediated PI3Kgamma-dependent phosphorylation of vimentin. Eur J Immunol 39:1136–1146CrossRefPubMedGoogle Scholar
  12. Benistant C, Chapuis H, Roche S (2000) A specific function for phosphatidylinositol 3-kinase alpha (p85alpha-p110alpha) in cell survival and for phosphatidylinositol 3-kinase beta (p85alpha-p110beta) in de novo DNA synthesis of human colon carcinoma cells. Oncogene 19:5083–5090CrossRefPubMedGoogle Scholar
  13. Berenjeno IM, Vanhaesebroeck B (2009) PI3K regulatory subunits lose control in cancer. Cancer Cell 16:449–450CrossRefPubMedGoogle Scholar
  14. Berwick DC, Dell GC, Welsh GI, Heesom KJ, Hers I, Fletcher LM, Cooke FT, Tavare JM (2004) Protein kinase B phosphorylation of PIKfyve regulates the trafficking of GLUT4 vesicles. J Cell Sci 117:5985–5993CrossRefPubMedGoogle Scholar
  15. 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 274:10963–10968CrossRefPubMedGoogle Scholar
  16. Bilancio A, Okkenhaug K, Camps M, Emery JL, Ruckle T, Rommel C, Vanhaesebroeck B (2006) Key role of the p110delta isoform of PI3K in B-cell antigen and IL-4 receptor signaling: comparative analysis of genetic and pharmacologic interference with p110delta function in B cells. Blood 107:642–650CrossRefPubMedGoogle Scholar
  17. Bjornholm M, Kawano Y, Lehtihet M, Zierath JR (1997) Insulin receptor substrate-1 phosphorylation and phosphatidylinositol 3-kinase activity in skeletal muscle from NIDDM subjects after in vivo insulin stimulation. Diabetes 46:524–527CrossRefPubMedGoogle Scholar
  18. Bohnacker T, Marone R, Collmann E, Calvez R, Hirsch E, Wymann MP (2009) PI3Kgamma adaptor subunits define coupling to degranulation and cell motility by distinct PtdIns(3,4,5)P3 pools in mast cells. Sci Signal 2:ra27Google Scholar
  19. Borlado LR, Redondo C, Alvarez B, Jimenez C, Criado LM, Flores J, Marcos MA, Martinez AC, Balomenos D, Carrera AC (2000) Increased phosphoinositide 3-kinase activity induces a lymphoproliferative disorder and contributes to tumor generation in vivo. Faseb J 14:895–903PubMedGoogle Scholar
  20. Brachmann SM, Ueki K, Engelman JA, Kahn RC, Cantley LC (2005) Phosphoinositide 3-kinase catalytic subunit deletion and regulatory subunit deletion have opposite effects on insulin sensitivity in mice. Mol Cell Biol 25:1596–1607CrossRefPubMedGoogle Scholar
  21. Brennan FM, Feldmann M (1996) Cytokines in autoimmunity. Curr Opin Immunol 8:872–877CrossRefPubMedGoogle Scholar
  22. Bristow MR, Ginsburg R, Minobe W, Cubicciotti RS, Sageman WS, Lurie K, Billingham ME, Harrison DC, Stinson EB (1982) Decreased catecholamine sensitivity and beta-adrenergic-receptor density in failing human hearts. N Engl J Med 307:205–211CrossRefPubMedGoogle Scholar
  23. Brodde OE, Bruck H, Leineweber K (2006) Cardiac adrenoceptors: physiological and pathophysiological relevance. J Pharmacol Sci 100:323–337CrossRefPubMedGoogle Scholar
  24. Camps M, Ruckle T, Ji H, Ardissone V, Rintelen F, Shaw J, Ferrandi C, Chabert C, Gillieron C, Francon B et al (2005) Blockade of PI3Kgamma suppresses joint inflammation and damage in mouse models of rheumatoid arthritis. Nature medicine 11:936–943PubMedGoogle Scholar
  25. Carvalho S, Milanezi F, Costa JL, Amendoeira I, Schmitt F (2010) PIKing the right isoform: the emergent role of the p110beta subunit in breast cancer. Virchows Arch 456:235–243CrossRefPubMedGoogle Scholar
  26. Chagpar RB, Links PH, Pastor MC, Furber LA, Hawrysh AD, Chamberlain MD, Anderson DH (2010) Direct positive regulation of PTEN by the p85 subunit of phosphatidylinositol 3-kinase. Proc Natl Acad Sci USA 107:5471–5476CrossRefPubMedGoogle Scholar
  27. Chaussade C, Cho K, Mawson C, Rewcastle GW, Shepherd PR (2009) Functional differences between two classes of oncogenic mutation in the PIK3CA gene. Biochem Biophys Res Commun 381:577–581CrossRefPubMedGoogle Scholar
  28. Chen D, Mauvais-Jarvis F, Bluher M, Fisher SJ, Jozsi A, Goodyear LJ, Ueki K, Kahn CR (2004) p50alpha/p55alpha phosphoinositide 3-kinase knockout mice exhibit enhanced insulin sensitivity. Mol Cell Biol 24:320–329CrossRefPubMedGoogle Scholar
  29. Chen S, Wasserman DH, MacKintosh C, Sakamoto K (2011) Mice with AS160/TBC1D4-Thr649Ala knockin mutation are glucose intolerant with reduced insulin sensitivity and altered GLUT4 trafficking. Cell Metab 13:68–79CrossRefPubMedGoogle Scholar
  30. Cho H, Mu J, Kim JK, Thorvaldsen JL, Chu Q, Crenshaw EB 3rd, 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 292:1728–1731CrossRefPubMedGoogle Scholar
  31. Chu G, Lester JW, Young KB, Luo W, Zhai J, Kranias EG (2000) A single site (Ser16) phosphorylation in phospholamban is sufficient in mediating its maximal cardiac responses to beta-agonists. J Biol Chem 275:38938–38943CrossRefPubMedGoogle Scholar
  32. Ciraolo E, Iezzi M, Marone R, Marengo S, Curcio C, Costa C, Azzolino O, Gonella C, Rubinetto C Wu H et al (2008) Phosphoinositide 3-kinase p110beta activity: key role in metabolism and mammary gland cancer but not development. Sci Signal 1:ra3Google Scholar
  33. Clayton E, Bardi G, Bell SE, Chantry D, Downes CP, Gray A, Humphries LA, Rawlings D, Reynolds H, Vigorito E et al (2002) A crucial role for the p110delta subunit of phosphatidylinositol 3-kinase in B cell development and activation. J Exp Med 196:753–763CrossRefPubMedGoogle Scholar
  34. Condliffe AM, Davidson K, Anderson KE, Ellson CD, Crabbe T, Okkenhaug K, Vanhaesebroeck B, Turner M, Webb L, Wymann MP et al (2005) Sequential activation of class IB and class IA PI3K is important for the primed respiratory burst of human but not murine neutrophils. Blood 106:1432–1440CrossRefPubMedGoogle Scholar
  35. Condorelli G, Drusco A, Stassi G, Bellacosa A, Roncarati R, Iaccarino G, Russo MA, Gu Y, Dalton N, Chung C et al (2002) Akt induces enhanced myocardial contractility and cell size in vivo in transgenic mice. Proc Natl Acad Sci USA 99:12333–12338CrossRefPubMedGoogle Scholar
  36. Conti M, Beavo J (2007) Biochemistry and physiology of cyclic nucleotide phosphodiesterases: essential components in cyclic nucleotide signaling. Annu Rev Biochem 76:481–511CrossRefPubMedGoogle Scholar
  37. Costa C, Barberis L, Ambrogio C, Manazza AD, Patrucco E, Azzolino O, Neilsen PO, Ciraolo E, Altruda F, Prestwich GD et al (2007) Negative feedback regulation of Rac in leukocytes from mice expressing a constitutively active phosphatidylinositol 3-kinase gamma. Proc Natl Acad Sci USA 104:14354–14359CrossRefPubMedGoogle Scholar
  38. Crackower MA, Oudit GY, Kozieradzki I, Sarao R, Sun H, Sasaki T, Hirsch E, Suzuki A, Shioi T, Irie-Sasaki J et al (2002) Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways. Cell 110:737–749CrossRefPubMedGoogle Scholar
  39. Damilano F, Franco I, Perrino C, Schaefer K, Azzolino O, Carnevale D, Cifelli G, Carullo P, Ragona R, Ghigo A et al (2011) Distinct effects of leukocyte and cardiac phosphoinositide 3-kinase {gamma} activity in pressure overload-induced cardiac failure. Circulation 123:391–399CrossRefPubMedGoogle Scholar
  40. DeBosch B, Treskov I, Lupu TS, Weinheimer C, Kovacs A, Courtois M, Muslin AJ (2006) Akt1 is required for physiological cardiac growth. Circulation 113:2097–2104CrossRefPubMedGoogle Scholar
  41. De Gorter DJ, Beuling EA, Kersseboom R, Middendorp S, Van Gils JM, Hendriks RW, Pals ST, Spaargaren M (2007) Bruton’s tyrosine kinase and phospholipase Cgamma2 mediate chemokine-controlled B cell migration and homing. Immunity 26:93–104CrossRefPubMedGoogle Scholar
  42. Di Cristofano A, Kotsi P, Peng YF, Cordon-Cardo C, Elkon KB, Pandolfi PP (1999) Impaired Fas response and autoimmunity in Pten +/− mice. Science 285:2122–2125CrossRefPubMedGoogle Scholar
  43. Doherty DE (2004) The pathophysiology of airway dysfunction. Am J Med 117(Suppl 12A):11S–23SPubMedGoogle Scholar
  44. Doukas J, Eide L, Stebbins K, Racanelli-Layton A, Dellamary L, Martin M, Dneprovskaia E, Noronha G, Soll R, Wrasidlo W et al (2009) Aerosolized phosphoinositide 3-kinase gamma/delta inhibitor TG100–115 [3-[2,4-diamino-6-(3-hydroxyphenyl)pteridin-7-yl]phenol] as a therapeutic candidate for asthma and chronic obstructive pulmonary disease. J Pharmacol Exp Ther 328:758–765CrossRefPubMedGoogle Scholar
  45. Duan W, Aguinaldo Datiles AM, Leung BP, Vlahos CJ, Wong WS (2005) An anti-inflammatory role for a phosphoinositide 3-kinase inhibitor LY294002 in a mouse asthma model. Int Immunopharmacol 5:495–502CrossRefPubMedGoogle Scholar
  46. Edling CE, Selvaggi F, Buus R, Maffucci T, Di Sebastiano P, Friess H, Innocenti P, Kocher HM, Falasca M (2010) Key role of phosphoinositide 3-kinase class IB in pancreatic cancer. Clin Cancer Res 16:4928–4937CrossRefPubMedGoogle Scholar
  47. Edwards SW, Hallett MB (1997) Seeing the wood for the trees: the forgotten role of neutrophils in rheumatoid arthritis. Immunology today 18:320–324CrossRefPubMedGoogle Scholar
  48. Engelman JA, Luo J, Cantley LC (2006) The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet 7:606–619CrossRefPubMedGoogle Scholar
  49. Ezeamuzie CI, Sukumaran J, Philips E (2001) Effect of wortmannin on human eosinophil responses in vitro and on bronchial inflammation and airway hyperresponsiveness in Guinea pigs in vivo. Am J Respir Crit Care Med 164:1633–1639PubMedGoogle Scholar
  50. Farese RV, Sajan MP, Standaert ML (2005) Atypical protein kinase C in insulin action and insulin resistance. Biochem Soc Trans 33:350–353CrossRefPubMedGoogle Scholar
  51. Farese RV, Sajan MP, Yang H, Li P, Mastorides S, Gower WR Jr, Nimal S, Choi CS, Kim S, Shulman GI et al (2007) Muscle-specific knockout of PKC-lambda impairs glucose transport and induces metabolic and diabetic syndromes. J Clin Invest 117:2289–2301CrossRefPubMedGoogle Scholar
  52. Farghaly HS, Blagbrough IS, Medina-Tato DA, Watson ML (2008) Interleukin 13 increases contractility of murine tracheal smooth muscle by a phosphoinositide 3-kinase p110delta-dependent mechanism. Molecular pharmacology 73:1530–1537CrossRefPubMedGoogle Scholar
  53. Ferguson GJ, Milne L, Kulkarni S, Sasaki T, Walker S, Andrews S, Crabbe T, Finan P, Jones G, Jackson S et al (2007) PI(3)Kgamma has an important context-dependent role in neutrophil chemokinesis. Nature Cell Biol 9:86–91CrossRefPubMedGoogle Scholar
  54. Folli F, Saad MJ, Backer JM, Kahn CR (1993) Regulation of phosphatidylinositol 3-kinase activity in liver and muscle of animal models of insulin-resistant and insulin-deficient diabetes mellitus. J Clin Invest 92:1787–1794CrossRefPubMedGoogle Scholar
  55. Fougerat A, Gayral S, Gourdy P, Schambourg A, Ruckle T, Schwarz MK, Rommel C, Hirsch E, Arnal JF, Salles JP et al (2008) Genetic and pharmacological targeting of phosphoinositide 3-kinase-gamma reduces atherosclerosis and favors plaque stability by modulating inflammatory processes. Circulation 117:1310–1317CrossRefPubMedGoogle Scholar
  56. Foukas LC, Claret M, Pearce W, Okkenhaug K, Meek S, Peskett E, Sancho S, Smith AJ, Withers DJ, Vanhaesebroeck B (2006) Critical role for the p110alpha phosphoinositide-3-OH kinase in growth and metabolic regulation. Nature 441:366–370CrossRefPubMedGoogle Scholar
  57. Fruman DA, Cantley LC (2002) Phosphoinositide 3-kinase in immunological systems. Sem Immunol 14:7–18CrossRefGoogle Scholar
  58. Fruman DA, Mauvais-Jarvis F, Pollard DA, Yballe CM, Brazil D, Bronson RT, Kahn CR, Cantley LC (2000) Hypoglycaemia, liver necrosis and perinatal death in mice lacking all isoforms of phosphoinositide 3-kinase p85 alpha. Nat Genet 26:379–382CrossRefPubMedGoogle Scholar
  59. George S, Rochford JJ, Wolfrum C, Gray SL, Schinner S, Wilson JC, Soos MA, Murgatroyd PR, Williams RM, Acerini CL et al (2004) A family with severe insulin resistance and diabetes due to a mutation in AKT2. Science 304:1325–1328CrossRefPubMedGoogle Scholar
  60. Ghigo A, Hirsch E (2011) PI3Kgamma mediates cardiac cAMP compartmentalization through scaffloding of distinct phosphodiesterases. In Heart Failure Winter Meeting (Les Diablerets)Google Scholar
  61. Goodyear LJ, Giorgino F, Sherman LA, Carey J, Smith RJ, Dohm GL (1995) Insulin receptor phosphorylation, insulin receptor substrate-1 phosphorylation, and phosphatidylinositol 3-kinase activity are decreased in intact skeletal muscle strips from obese subjects. J Clin Invest 95:2195–2204CrossRefPubMedGoogle Scholar
  62. Gymnopoulos M, Elsliger MA, Vogt PK (2007) Rare cancer-specific mutations in PIK3CA show gain of function. Proc Natl Acad Sci USA 104:5569–5574CrossRefPubMedGoogle Scholar
  63. Harris ED Jr (1990) Rheumatoid arthritis. Pathophysiology and implications for therapy. N Engl J Med 322:1277–1289CrossRefPubMedGoogle Scholar
  64. Hayer S, Pundt N, Peters MA, Wunrau C, Kuhnel I, Neugebauer K, Strietholt S, Zwerina J, Korb A, Penninger J et al (2009) PI3K{gamma} regulates cartilage damage in chronic inflammatory arthritis. Faseb J 23:4288–4298CrossRefPubMedGoogle Scholar
  65. Henley T, Kovesdi D, Turner M (2008) B-cell responses to B-cell activation factor of the TNF family (BAFF) are impaired in the absence of PI3K delta. Eur J Immunol 38:3543–3548CrossRefPubMedGoogle Scholar
  66. Hill KM, Kalifa S, Das JR, Bhatti T, Gay M, Williams D, Taliferro-Smith L, De Marzo AM (2010) The role of PI 3-kinase p110beta in AKT signally, cell survival, and proliferation in human prostate cancer cells. Prostate 70:755–764PubMedGoogle Scholar
  67. Hirsch E, Katanaev VL, Garlanda C, Azzolino O, Pirola L, Silengo L, Sozzani S, Mantovani A, Altruda F, Wymann MP (2000) Central role for G protein-coupled phosphoinositide 3-kinase gamma in inflammation. Science 287:1049–1053CrossRefPubMedGoogle Scholar
  68. Hirsch E, Lembo G, Montrucchio G, Rommel C, Costa C, Barberis L (2006) Signaling through PI3Kgamma: a common platform for leukocyte, platelet and cardiovascular stress sensing. Thromb Haemost 95:29–35PubMedGoogle Scholar
  69. Hirsch E, Braccini L, Ciraolo E, Morello F, Perino A (2009) Twice upon a time: PI3K’s secret double life exposed. Trends Biochem Sci 34:244–248CrossRefPubMedGoogle Scholar
  70. Imamura T, Huang J, Usui I, Satoh H, Bever J, Olefsky JM (2003) Insulin-induced GLUT4 translocation involves protein kinase C-lambda-mediated functional coupling between Rab4 and the motor protein kinesin. Mol Cell Biol 23:4892–4900CrossRefPubMedGoogle Scholar
  71. 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 273:11548–11555CrossRefPubMedGoogle Scholar
  72. Jaiswal BS, Janakiraman V, Kljavin NM, Chaudhuri S, Stern HM, Wang W, Kan Z, Dbouk HA, Peters BA, Waring P et al (2009) Somatic mutations in p85alpha promote tumorigenesis through class IA PI3K activation. Cancer Cell 16:463–474CrossRefPubMedGoogle Scholar
  73. Ji H, Rintelen F, Waltzinger C, Bertschy Meier D, Bilancio A, Pearce W, Hirsch E, Wymann MP, Ruckle T, Camps M et al (2007) Inactivation of PI3Kgamma and PI3Kdelta distorts T-cell development and causes multiple organ inflammation. Blood 110:2940–2947CrossRefPubMedGoogle Scholar
  74. Jia S, Liu Z, Zhang S, Liu P, Zhang L, Lee SH, Zhang J, Signoretti S, Loda M, Roberts TM et al (2008) Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis. Nature 454:776–779PubMedGoogle Scholar
  75. Jou ST, Carpino N, Takahashi Y, Piekorz R, Chao JR, Carpino N, Wang D, Ihle JN (2002) Essential, nonredundant role for the phosphoinositide 3-kinase p110delta in signaling by the B-cell receptor complex. Mol Cell Biol 22:8580–8591CrossRefPubMedGoogle Scholar
  76. Kahn CR (1994) Banting lecture. Insulin action, diabetogenes, and the cause of type II diabetes. Diabetes 43:1066–1084CrossRefPubMedGoogle Scholar
  77. Kang S, Denley A, Vanhaesebroeck B, Vogt PK (2006) Oncogenic transformation induced by the p110beta, -gamma, and -delta isoforms of class I phosphoinositide 3-kinase. Proc Natl Acad Sci USA 103:1289–1294CrossRefPubMedGoogle Scholar
  78. Kerfant BG, Zhao D, Lorenzen-Schmidt I, Wilson LS, Cai S, Chen SR, Maurice DH, Backx PH (2007) PI3Kgamma is required for PDE4, not PDE3, activity in subcellular microdomains containing the sarcoplasmic reticular calcium ATPase in cardiomyocytes. Circ Res 101:400–408CrossRefPubMedGoogle Scholar
  79. Kerouz NJ, Horsch D, Pons S, Kahn CR (1997) Differential regulation of insulin receptor substrates-1 and -2 (IRS-1 and IRS-2) and phosphatidylinositol 3-kinase isoforms in liver and muscle of the obese diabetic (ob/ob) mouse. J Clin Invest 100:3164–3172CrossRefPubMedGoogle Scholar
  80. Knight ZA, Gonzalez B, Feldman ME, Zunder ER, Goldenberg DD, Williams O, Loewith R, Stokoe D, Balla A, Toth B et al (2006) A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell 125:733–747CrossRefPubMedGoogle Scholar
  81. Knobbe CB, Reifenberger G (2003) Genetic alterations and aberrant expression of genes related to the phosphatidyl-inositol-3'-kinase/protein kinase B (Akt) signal transduction pathway in glioblastomas. Brain Pathol 13:507–518CrossRefPubMedGoogle Scholar
  82. Kotani K, Ogawa W, Hino Y, Kitamura T, Ueno H, Sano W, Sutherland C, Granner DK, Kasuga M (1999) Dominant negative forms of Akt (protein kinase B) and atypical protein kinase Clambda do not prevent insulin inhibition of phosphoenolpyruvate carboxykinase gene transcription. J Biol Chem 274:21305–21312CrossRefPubMedGoogle Scholar
  83. Kurlawalla-Martinez C, Stiles B, Wang Y, Devaskar SU, Kahn BB, Wu H (2005) Insulin hypersensitivity and resistance to streptozotocin-induced diabetes in mice lacking PTEN in adipose tissue. Mol Cell Biol 25:2498–2510CrossRefPubMedGoogle Scholar
  84. Laffargue M, Calvez R, Finan P, Trifilieff A, Barbier M, Altruda F, Hirsch E, Wymann MP (2002) Phosphoinositide 3-kinase gamma is an essential amplifier of mast cell function. Immunity 16:441–451CrossRefPubMedGoogle Scholar
  85. Lee KS, Lee HK, Hayflick JS, Lee YC, Puri KD (2006) Inhibition of phosphoinositide 3-kinase delta attenuates allergic airway inflammation and hyperresponsiveness in murine asthma model. Faseb J 20:455–465CrossRefPubMedGoogle Scholar
  86. Lee SH, Poulogiannis G, Pyne S, Jia S, Zou L, Signoretti S, Loda M, Cantley LC, Roberts TM (2010) A constitutively activated form of the p110beta isoform of PI3-kinase induces prostatic intraepithelial neoplasia in mice. Proc Natl Acad Sci USA 107:11002–11007CrossRefPubMedGoogle Scholar
  87. Lefkowitz RJ, Whalen EJ (2004) beta-arrestins: traffic cops of cell signaling. Curr Opin Cell Biol 16:162–168CrossRefPubMedGoogle Scholar
  88. Li Z, Jiang H, Xie W, Zhang Z, Smrcka AV, Wu D (2000) Roles of PLC-beta2 and -beta3 and PI3Kgamma in chemoattractant-mediated signal transduction. Science 287:1046–1049CrossRefPubMedGoogle Scholar
  89. Lim DH, Cho JY, Song DJ, Lee SY, Miller M, Broide DH (2009) PI3K gamma-deficient mice have reduced levels of allergen-induced eosinophilic inflammation and airway remodeling. Am J Physiol 296:L210–L219Google Scholar
  90. Lin RC, Weeks KL, Gao XM, Williams RB, Bernardo BC, Kiriazis H, Matthews VB, Woodcock EA, Bouwman RD, Mollica JP et al (2010) PI3K(p110 alpha) protects against myocardial infarction-induced heart failure: identification of PI3K-regulated miRNA and mRNA. Arterioscler Thromb Vasc Biol 30:724–732CrossRefPubMedGoogle Scholar
  91. Link W, Rosado A, Fominaya J, Thomas JE, Carnero A (2005) Membrane localization of all class I PI 3-kinase isoforms suppresses c-Myc-induced apoptosis in Rat1 fibroblasts via Akt. J Cell Biochem 95:979–989CrossRefPubMedGoogle Scholar
  92. Liu K, Wakeland EK (2001) Delineation of the pathogenesis of systemic lupus erythematosus by using murine models. Adv Exp Med Biol 490:1–6CrossRefPubMedGoogle Scholar
  93. Liu L, Puri KD, Penninger JM, Kubes P (2007) Leukocyte PI3Kgamma and PI3Kdelta have temporally distinct roles for leukocyte recruitment in vivo. Blood 110:1191–1198CrossRefPubMedGoogle Scholar
  94. Liu D, Zhang T, Marshall AJ, Okkenhaug K, Vanhaesebroeck B, Uzonna JE (2009) The p110delta isoform of phosphatidylinositol 3-kinase controls susceptibility to Leishmania major by regulating expansion and tissue homing of regulatory T cells. J Immunol 183:1921–1933CrossRefPubMedGoogle Scholar
  95. Locke NR, Patterson SJ, Hamilton MJ, Sly LM, Krystal G, Levings MK (2009) SHIP regulates the reciprocal development of T regulatory and Th17 cells. J Immunol 183:975–983CrossRefPubMedGoogle Scholar
  96. Maffucci T, Brancaccio A, Piccolo E, Stein RC, Falasca M (2003) Insulin induces phosphatidylinositol-3-phosphate formation through TC10 activation. EMBO J 22:4178–4189CrossRefPubMedGoogle Scholar
  97. Marwick JA, Caramori G, Stevenson CS, Casolari P, Jazrawi E, Barnes PJ, Ito K, Adcock IM, Kirkham PA, Papi A (2009) Inhibition of PI3Kdelta restores glucocorticoid function in smoking-induced airway inflammation in mice. Am J Respir Crit Care Med 179:542–548CrossRefPubMedGoogle Scholar
  98. Marwick JA, Caramori G, Casolari P, Mazzoni F, Kirkham PA, Adcock IM, Chung KF, Papi A (2010) A role for phosphoinositol 3-kinase delta in the impairment of glucocorticoid responsiveness in patients with chronic obstructive pulmonary disease. J Allergy Clin Immunol 125:1146–1153CrossRefPubMedGoogle Scholar
  99. Marx SO, Reiken S, Hisamatsu Y, Jayaraman T, Burkhoff D, Rosemblit N, Marks AR (2000) PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts. Cell 101:365–376CrossRefPubMedGoogle Scholar
  100. Matsui T, Li L, Wu JC, Cook SA, Nagoshi T, Picard MH, Liao R, Rosenzweig A (2002) Phenotypic spectrum caused by transgenic overexpression of activated Akt in the heart. J Biol Chem 277:22896–22901CrossRefPubMedGoogle Scholar
  101. McMullen JR, Shioi T, Zhang L, Tarnavski O, Sherwood MC, Kang PM, Izumo S (2003) Phosphoinositide 3-kinase(p110alpha) plays a critical role for the induction of physiological, but not pathological, cardiac hypertrophy. Proc Natl Acad Sci USA 100:12355–12360CrossRefPubMedGoogle Scholar
  102. McMullen JR, Amirahmadi F, Woodcock EA, Schinke-Braun M, Bouwman RD, Hewitt KA, Mollica JP, Zhang L, Zhang Y, Shioi T et al (2007) Protective effects of exercise and phosphoinositide 3-kinase(p110alpha) signaling in dilated and hypertrophic cardiomyopathy. Proc Natl Acad Sci USA 104:612–617CrossRefPubMedGoogle Scholar
  103. Mishra RK, Scaife JE, Harb Z, Gray BC, Djukanovic R, Dent G (2005) Differential dependence of eosinophil chemotactic responses on phosphoinositide 3-kinase (PI3K). Allergy 60:1204–1207CrossRefPubMedGoogle Scholar
  104. Morrow CJ, Gray A, Dive C (2005) Comparison of phosphatidylinositol-3-kinase signalling within a panel of human colorectal cancer cell lines with mutant or wild-type PIK3CA. FEBS Lett 579:5123–5128CrossRefPubMedGoogle Scholar
  105. Myers MG Jr, White MF (1993) The new elements of insulin signaling. Insulin receptor substrate-1 and proteins with SH2 domains. Diabetes 42:643–650CrossRefPubMedGoogle Scholar
  106. Myers MG Jr, Backer JM, Sun XJ, Shoelson S, Hu P, Schlessinger J, Yoakim M, Schaffhausen B, White MF (1992) IRS-1 activates phosphatidylinositol 3'-kinase by associating with src homology 2 domains of p85. Proc Natl Acad Sci USA 89:10350–10354CrossRefPubMedGoogle Scholar
  107. Naga Prasad SV, Esposito G, Mao L, Koch WJ, Rockman HA (2000) Gbetagamma-dependent phosphoinositide 3-kinase activation in hearts with in vivo pressure overload hypertrophy. J Biol Chem 275:4693–4698CrossRefGoogle Scholar
  108. Naga Prasad SV, Barak LS, Rapacciuolo A, Caron MG, Rockman HA (2001) Agonist-dependent recruitment of phosphoinositide 3-kinase to the membrane by beta-adrenergic receptor kinase 1. A role in receptor sequestration. J Biol Chem 276:18953–18959CrossRefGoogle Scholar
  109. Naga Prasad SV, Laporte SA, Chamberlain D, Caron MG, Barak L, Rockman HA (2002) Phosphoinositide 3-kinase regulates beta2-adrenergic receptor endocytosis by AP-2 recruitment to the receptor/beta-arrestin complex. J Cell Biol 158:563–575CrossRefGoogle Scholar
  110. Nakae J, Kitamura T, Silver DL, Accili D (2001) The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose-6-phosphatase expression. J Clin Invest 108:1359–1367PubMedGoogle Scholar
  111. Nienaber JJ, Tachibana H, Naga Prasad SV, Esposito G, Wu D, Mao L, Rockman HA (2003) Inhibition of receptor-localized PI3K preserves cardiac beta-adrenergic receptor function and ameliorates pressure overload heart failure. J Clin Invest 112:1067–1079PubMedGoogle Scholar
  112. Nombela-Arrieta C, Lacalle RA, Montoya MC, Kunisaki Y, Megias D, Marques M, Carrera AC, Manes S, Fukui Y, Martinez AC et al (2004) Differential requirements for DOCK2 and phosphoinositide-3-kinase gamma during T and B lymphocyte homing. Immunity 21:429–441CrossRefPubMedGoogle Scholar
  113. Oak JS, Deane JA, Kharas MG, Luo J, Lane TE, Cantley LC, Fruman DA (2006) Sjogren’s syndrome-like disease in mice with T cells lacking class 1A phosphoinositide-3-kinase. Proc Natl Acad Sci USA 103:16882–16887CrossRefPubMedGoogle Scholar
  114. Okada T, Sakuma L, Fukui Y, Hazeki O, Ui M (1994) Blockage of chemotactic peptide-induced stimulation of neutrophils by wortmannin as a result of selective inhibition of phosphatidylinositol 3-kinase. J Biol Chem 269:3563–3567PubMedGoogle Scholar
  115. Okkenhaug K, Bilancio A, Farjot G, Priddle H, Sancho S, Peskett E, Pearce W, Meek SE, Salpekar A, Waterfield MD et al (2002) Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. Science 297:1031–1034PubMedGoogle Scholar
  116. Okkenhaug K, Patton DT, Bilancio A, Garcon F, Rowan WC, Vanhaesebroeck B (2006) The p110delta isoform of phosphoinositide 3-kinase controls clonal expansion and differentiation of Th cells. J Immunol 177:5122–5128PubMedGoogle Scholar
  117. Omori SA, Cato MH, Anzelon-Mills A, Puri KD, Shapiro-Shelef M, Calame K, Rickert RC (2006) Regulation of class-switch recombination and plasma cell differentiation by phosphatidylinositol 3-kinase signaling. Immunity 25:545–557CrossRefPubMedGoogle Scholar
  118. Palframan RT, Collins PD, Severs NJ, Rothery S, Williams TJ, Rankin SM (1998) Mechanisms of acute eosinophil mobilization from the bone marrow stimulated by interleukin 5: the role of specific adhesion molecules and phosphatidylinositol 3-kinase. J Exp Med 188:1621–1632CrossRefPubMedGoogle Scholar
  119. Patrucco E, Notte A, Barberis L, Selvetella G, Maffei A, Brancaccio M, Marengo S, Russo G, Azzolino O, Rybalkin SD et al (2004) PI3Kgamma modulates the cardiac response to chronic pressure overload by distinct kinase-dependent and -independent effects. Cell 118:375–387CrossRefPubMedGoogle Scholar
  120. Patton DT, Garden OA, Pearce WP, Clough LE, Monk CR, Leung E, Rowan WC, Sancho S, Walker LS, Vanhaesebroeck B et al (2006) Cutting edge: the phosphoinositide 3-kinase p110 delta is critical for the function of CD4 + CD25 + Foxp3 + regulatory T cells. J Immunol 177:6598–6602PubMedGoogle Scholar
  121. Perino A, Ghigo A, Ferrero E, Morello F, Santulli G, Baillie GS, Damilano F, Dunlop AJ, Pawson C, Walser R et al (2011) Integrating cardiac PIP3 and cAMP signaling through a PKA anchoring function of p110γ. Mol Cell 42(1):84–95CrossRefPubMedGoogle Scholar
  122. Perrino C, Naga Prasad SV, Patel M, Wolf MJ, Rockman HA (2005a) Targeted inhibition of beta-adrenergic receptor kinase-1-associated phosphoinositide-3 kinase activity preserves beta-adrenergic receptor signaling and prolongs survival in heart failure induced by calsequestrin overexpression. J Am Coll Cardiol 45:1862–1870CrossRefGoogle Scholar
  123. Perrino C, Naga Prasad SV, Schroder JN, Hata JA, Milano C, Rockman HA (2005b) Restoration of beta-adrenergic receptor signaling and contractile function in heart failure by disruption of the betaARK1/phosphoinositide 3-kinase complex. Circulation 111:2579–2587CrossRefGoogle Scholar
  124. Phu T, Haeryfar SM, Musgrave BL, Hoskin DW (2001) Phosphatidylinositol 3-kinase inhibitors prevent mouse cytotoxic T-cell development in vitro. J Leukoc Biol 69:803–814PubMedGoogle Scholar
  125. Pinho V, Souza DG, Barsante MM, Hamer FP, De Freitas MS, Rossi AG, Teixeira MM (2005) Phosphoinositide-3 kinases critically regulate the recruitment and survival of eosinophils in vivo: importance for the resolution of allergic inflammation. J Leukoc Biol 77:800–810CrossRefPubMedGoogle Scholar
  126. Puri KD, Doggett TA, Douangpanya J, Hou Y, Tino WT, Wilson T, Graf T, Clayton E, Turner M, Hayflick JS et al (2004) Mechanisms and implications of phosphoinositide 3-kinase delta in promoting neutrophil trafficking into inflamed tissue. Blood 103:3448–3456CrossRefPubMedGoogle Scholar
  127. Puri KD, Doggett TA, Huang CY, Douangpanya J, Hayflick JS, Turner M, Penninger J, Diacovo TG (2005) The role of endothelial PI3Kgamma activity in neutrophil trafficking. Blood 106:150–157CrossRefPubMedGoogle Scholar
  128. Randis TM, Puri KD, Zhou H, Diacovo TG (2008) Role of PI3Kdelta and PI3Kgamma in inflammatory arthritis and tissue localization of neutrophils. Eur J Immunol 38:1215–1224CrossRefPubMedGoogle Scholar
  129. Reif K, Okkenhaug K, Sasaki T, Penninger JM, Vanhaesebroeck B, Cyster JG (2004) Cutting edge: differential roles for phosphoinositide 3-kinases, p110gamma and p110delta, in lymphocyte chemotaxis and homing. J Immunol 173:2236–2240PubMedGoogle Scholar
  130. Rockman HA, Koch WJ, Lefkowitz RJ (2002) Seven-transmembrane-spanning receptors and heart function. Nature 415:206–212CrossRefPubMedGoogle Scholar
  131. Rommel C, Camps M, Ji H (2007) PI3K delta and PI3K gamma: partners in crime in inflammation in rheumatoid arthritis and beyond? Nat Rev Immunol 7:191–201CrossRefPubMedGoogle Scholar
  132. Saal LH, Holm K, Maurer M, Memeo L, Su T, Wang X, Yu JS, Malmstrom PO, Mansukhani M, Enoksson J et al (2005) PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res 65:2554–2559CrossRefPubMedGoogle Scholar
  133. Sadhu C, Masinovsky B, Dick K, Sowell CG, Staunton DE (2003) Essential role of phosphoinositide 3-kinase delta in neutrophil directional movement. J Immunol 170:2647–2654PubMedGoogle Scholar
  134. Samuels Y, Wang Z, Bardelli A, Silliman N, Ptak J, Szabo S, Yan H, Gazdar A, Powell SM, Riggins GJ et al (2004) High frequency of mutations of the PIK3CA gene in human cancers. Science 304:554CrossRefPubMedGoogle Scholar
  135. Sano H, Kane S, Sano E, Miinea CP, Asara JM, Lane WS, Garner CW, Lienhard GE (2003) Insulin-stimulated phosphorylation of a Rab GTPase-activating protein regulates GLUT4 translocation. J Biol Chem 278:14599–14602CrossRefPubMedGoogle Scholar
  136. Sasaki T, Irie-Sasaki J, Jones RG, Oliveira-dos-Santos AJ, Stanford WL, Bolon B, Wakeham A, Itie A, Bouchard D, Kozieradzki I et al (2000) Function of PI3Kgamma in thymocyte development, T cell activation, and neutrophil migration. Science 287:1040–1046CrossRefPubMedGoogle Scholar
  137. Scott JD, Pawson T (2009) Cell signaling in space and time: where proteins come together and when they’re apart. Science 326:1220–1224CrossRefPubMedGoogle Scholar
  138. Shepherd PR (2005) Mechanisms regulating phosphoinositide 3-kinase signalling in insulin-sensitive tissues. Acta Physiol Scand 183:3–12CrossRefPubMedGoogle Scholar
  139. Shi J, Cinek T, Truitt KE, Imboden JB (1997) Wortmannin, a phosphatidylinositol 3-kinase inhibitor, blocks antigen-mediated, but not CD3 monoclonal antibody-induced, activation of murine CD4 + T cells. J Immunol 158:4688–4695PubMedGoogle Scholar
  140. Shioi T, Kang PM, Douglas PS, Hampe J, Yballe CM, Lawitts J, Cantley LC, Izumo S (2000) The conserved phosphoinositide 3-kinase pathway determines heart size in mice. EMBO J 19:2537–2548CrossRefPubMedGoogle Scholar
  141. Silvestris N, Tommasi S, Petriella D, Santini D, Fistola E, Russo A, Numico G, Tonini G, Maiello E, Colucci G (2009) The dark side of the moon: the PI3K/PTEN/AKT pathway in colorectal carcinoma. Oncology 77(Suppl 1):69–74CrossRefPubMedGoogle Scholar
  142. Sinclair LV, Finlay D, Feijoo C, Cornish GH, Gray A, Ager A, Okkenhaug K, Hagenbeek TJ, Spits H, Cantrell DA (2008) Phosphatidylinositol-3-OH kinase and nutrient-sensing mTOR pathways control T lymphocyte trafficking. Nat Immunol 9:513–521CrossRefPubMedGoogle Scholar
  143. Siragusa M, Katare R, Meloni M, Damilano F, Hirsch E, Emanueli C, Madeddu P (2010) Involvement of phosphoinositide 3-kinase gamma in angiogenesis and healing of experimental myocardial infarction in mice. Circ Res 106:757–768CrossRefPubMedGoogle Scholar
  144. Skeberdis VA, Gendviliene V, Zablockaite D, Treinys R, Macianskiene R, Bogdelis A, Jurevicius J, Fischmeister R (2008) beta3-adrenergic receptor activation increases human atrial tissue contractility and stimulates the L-type Ca2 + current. J Clin Invest 118:3219–3227PubMedGoogle Scholar
  145. Smith LD, Hickman ES, Parry RV, Westwick J, Ward SG (2007) PI3Kgamma is the dominant isoform involved in migratory responses of human T lymphocytes: effects of ex vivo maintenance and limitations of non-viral delivery of siRNA. Cell Signal 19:2528–2539CrossRefPubMedGoogle Scholar
  146. Sopasakis VR, Liu P, Suzuki R, Kondo T, Winnay J, Tran TT, Asano T, Smyth G, Sajan MP, Farese RV et al (2010) Specific roles of the p110alpha isoform of phosphatidylinsositol 3-kinase in hepatic insulin signaling and metabolic regulation. Cell Metab 11:220–230CrossRefPubMedGoogle Scholar
  147. Stelzer JE, Patel JR, Walker JW, Moss RL (2007) Differential roles of cardiac myosin-binding protein C and cardiac troponin I in the myofibrillar force responses to protein kinase A phosphorylation. Circ Res 101:503–511CrossRefPubMedGoogle Scholar
  148. Stenkula KG, Lizunov VA, Cushman SW, Zimmerberg J (2010) Insulin controls the spatial distribution of GLUT4 on the cell surface through regulation of its postfusion dispersal. Cell Metab 12:250–259CrossRefPubMedGoogle Scholar
  149. Sujobert P, Bardet V, Cornillet-Lefebvre P, Hayflick JS, Prie N, Verdier F, Vanhaesebroeck B, Muller O, Pesce F, Ifrah N et al (2005) Essential role for the p110delta isoform in phosphoinositide 3-kinase activation and cell proliferation in acute myeloid leukemia. Blood 106:1063–1066CrossRefPubMedGoogle Scholar
  150. Sun XJ, Crimmins DL, Myers MG Jr, Miralpeix M, White MF (1993) Pleiotropic insulin signals are engaged by multisite phosphorylation of IRS-1. Mol Cell Biol 13:7418–7428PubMedGoogle Scholar
  151. Szekanecz Z, Kim J, Koch AE (2003) Chemokines and chemokine receptors in rheumatoid arthritis. Sem Immunol 15:15–21CrossRefGoogle Scholar
  152. Takeda M, Ito W, Tanabe M, Ueki S, Kato H, Kihara J, Tanigai T, Chiba T, Yamaguchi K, Kayaba H et al (2009) Allergic airway hyperresponsiveness, inflammation, and remodeling do not develop in phosphoinositide 3-kinase gamma-deficient mice. J Allergy Clin Immunol 123:805–812CrossRefPubMedGoogle Scholar
  153. Taniguchi CM, Emanuelli B, Kahn CR (2006) Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol 7:85–96CrossRefPubMedGoogle Scholar
  154. Terauchi Y, Tsuji Y, Satoh S, Minoura H, Murakami K, Okuno A, Inukai K, Asano T, Kaburagi Y, Ueki K et al (1999) Increased insulin sensitivity and hypoglycaemia in mice lacking the p85 alpha subunit of phosphoinositide 3-kinase. Nat Genet 21:230–235CrossRefPubMedGoogle Scholar
  155. Tigani B, Hannon JP, Mazzoni L, Fozard JR (2001) Effects of wortmannin on airways inflammation induced by allergen in actively sensitised Brown Norway rats. Eur J Pharmacol 433:217–223CrossRefPubMedGoogle Scholar
  156. Tkaczyk C, Beaven MA, Brachman SM, Metcalfe DD, Gilfillan AM (2003) The phospholipase C gamma 1-dependent pathway of Fc epsilon RI-mediated mast cell activation is regulated independently of phosphatidylinositol 3-kinase. J Biol Chem 278:48474–48484CrossRefPubMedGoogle Scholar
  157. Ueki K, Yballe CM, Brachmann SM, Vicent D, Watt JM, Kahn CR, Cantley LC (2002) Increased insulin sensitivity in mice lacking p85beta subunit of phosphoinositide 3-kinase. Proc Natl Acad Sci USA 99:419–424CrossRefPubMedGoogle Scholar
  158. Vasudevan KM, Barbie DA, Davies MA, Rabinovsky R, McNear CJ, Kim JJ, Hennessy BT, Tseng H, Pochanard P, Kim SY et al (2009) AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer. Cancer Cell 16:21–32CrossRefPubMedGoogle Scholar
  159. Velasco A, Bussaglia E, Pallares J, Dolcet X, Llobet D, Encinas M, Llecha N, Palacios J, Prat J, Matias-Guiu X (2006) PIK3CA gene mutations in endometrial carcinoma: correlation with PTEN and K-RAS alterations. Hum Pathol 37:1465–1472CrossRefPubMedGoogle Scholar
  160. Voigt P, Dorner MB, Schaefer M (2006) Characterization of p87PIKAP, a novel regulatory subunit of phosphoinositide 3-kinase gamma that is highly expressed in heart and interacts with PDE3B. J Biol Chem 281:9977–9986CrossRefPubMedGoogle Scholar
  161. Webb LM, Vigorito E, Wymann MP, Hirsch E, Turner M (2005) Cutting edge: T cell development requires the combined activities of the p110gamma and p110delta catalytic isoforms of phosphatidylinositol 3-kinase. J Immunol 175:2783–2787PubMedGoogle Scholar
  162. Wee S, Wiederschain D, Maira SM, Loo A, Miller C, DeBeaumont R, Stegmeier F, Yao YM, Lengauer C (2008) PTEN-deficient cancers depend on PIK3CB. Proc Natl Acad Sci USA 105:13057–13062CrossRefPubMedGoogle Scholar
  163. Wong KK, Engelman JA, Cantley LC (2010) Targeting the PI3K signaling pathway in cancer. Curr Opin Genet Dev 20:87–90CrossRefPubMedGoogle Scholar
  164. Zhang TT, Okkenhaug K, Nashed BF, Puri KD, Knight ZA, Shokat KM, Vanhaesebroeck B, Marshall AJ (2008) Genetic or pharmaceutical blockade of p110delta phosphoinositide 3-kinase enhances IgE production. J Allergy Clin Immunol 122:811–819 e812Google Scholar
  165. Zhao L, Vogt PK (2008) Helical domain and kinase domain mutations in p110alpha of phosphatidylinositol 3-kinase induce gain of function by different mechanisms. Proc Natl Acad Sci USA 105:2652–2657CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  • Alessandra Ghigo
    • 1
  • Fulvio Morello
    • 1
  • Alessia Perino
    • 1
  • Emilio Hirsch
    • 1
    Email author
  1. 1.Molecular Biotechnology Center, Department of Genetics, Biology and BiochemistryUniversity of TorinoTorinoItaly

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