Advertisement

PI3K: From the Bench to the Clinic and Back

  • Bart Vanhaesebroeck
  • Peter K. Vogt
  • Christian Rommel
Chapter
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 347)

Abstract

From humble beginnings over 25 years ago as a lipid kinase activity associated with certain oncoproteins, PI3K (phosphoinositide 3-kinase) has been catapulted to the forefront of drug development in cancer, immunity and thrombosis, with the first clinical trials of PI3K pathway inhibitors now in progress. Here, we give a brief overview of some key discoveries in the PI3K area and their impact, and include thoughts on the current state of the field, and where it could go from here.

PI3K has become a very intense area of research, with over 2,000 publications on PI3K in PubMed for 2009 alone. The expectations for a therapeutic impact of intervention with PI3K activity are high, and progress in the clinical arena is being monitored by many. However, targeted therapies almost invariably encounter roadblocks, often exposing unresolved questions in the basic understanding of the target. PI3K will most likely be no exception. Below, we describe some of these early “surprises” and how these inform and shape basic science investigations.

Keywords

PI3K Inhibitor PI3K Pathway PI3K Signalling PI3K Activity FYVE Domain 
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.

Notes

Acknowledgements

The authors apologize to the many authors whose primary research papers have not been cited due to space constraints. Research in the laboratory of BV is supported by Cancer Research UK, the MRC and BBSRC, EU, EMBO and the Ludwig Institute for Cancer Research. PKV is supported by grants from the National Cancer Institute and by The Stein Foundation. This is manuscript 20614 of The Scripps Research Institute. CR is supported by Intellikine Inc., a privately held biopharmaceutical company dedicated to the development of novel molecular targeted therapeutics.

References

  1. 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
  2. Alessi DR, Deak M, Casamayor A, Caudwell FB, Morrice N, Norman DG, Gaffney P, Reese CB, MacDougall CN, Harbison D, Ashworth A, Bownes M (1997a) 3-Phosphoinositide-dependent protein kinase-1 (PDK1): structural and functional homology with the Drosophila DSTPK61 kinase. Curr Biol 7:776–789PubMedGoogle Scholar
  3. Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB, Cohen P (1997b) Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol 7:261–269PubMedGoogle Scholar
  4. Andjelkovic M, Alessi DR, Meier R, Fernandez A, Lamb NJ, Frech M, Cron P, Cohen P, Lucocq JM, Hemmings BA (1997) Role of translocation in the activation and function of protein kinase B. J Biol Chem 272:31515–31524PubMedGoogle Scholar
  5. Arcaro A, Wymann MP (1993) Wortmannin is a potent phosphatidylinositol 3-kinase inhibitor: the role of phosphatidylinositol 3,4,5-trisphosphate in neutrophil responses. Biochem J 296(Pt 2):297–301PubMedGoogle Scholar
  6. Arcaro A, Volinia S, Zvelebil MJ, Stein R, Watton SJ, Layton MJ, Gout I, Ahmadi K, Downward J, Waterfield MD (1998) Human phosphoinositide 3-kinase C2beta, the role of calcium and the C2 domain in enzyme activity. J Biol Chem 273:33082–33090PubMedGoogle Scholar
  7. Auger KR, Serunian LA, Soltoff SP, Libby P, Cantley LC (1989) PDGF-dependent tyrosine phosphorylation stimulates production of novel polyphosphoinositides in intact cells. Cell 57:167–175PubMedGoogle Scholar
  8. 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
  9. Bielas SL, Silhavy JL, Brancati F, Kisseleva MV, Al-Gazali L, Sztriha L, Bayoumi RA, Zaki MS, Abdel-Aleem A, Rosti RO, Kayserili H, Swistun D, Scott LC, Bertini E, Boltshauser E, Fazzi E, Travaglini L, Field SJ, Gayral S, Jacoby M, Schurmans S, Dallapiccola B, Majerus PW, Valente EM, Gleeson JG (2009) Mutations in INPP5E, encoding inositol polyphosphate-5-phosphatase E, link phosphatidyl inositol signaling to the ciliopathies. Nat Genet 41:1032–1036PubMedGoogle Scholar
  10. Birkeland HC, Stenmark H (2004) Protein targeting to endosomes and phagosomes via FYVE and PX domains. Curr Top Microbiol Immunol 282:89–115PubMedGoogle Scholar
  11. Brazil DP, Hemmings BA (2001) Ten years of protein kinase B signalling: a hard Akt to follow. Trends Biochem Sci 26:657–664PubMedGoogle Scholar
  12. Brown RA, Ho LK, Weber-Hall SJ, Shipley JM, Fry MJ (1997) Identification and cDNA cloning of a novel mammalian C2 domain-containing phosphoinositide 3-kinase, HsC2-PI3K. Biochem Biophys Res Commun 233:537–544PubMedGoogle Scholar
  13. Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 96:857–868PubMedGoogle Scholar
  14. Burgering BM, Coffer PJ (1995) Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature 376:599–602PubMedGoogle Scholar
  15. Byfield MP, Murray JT, Backer JM (2005) hVps34 is a nutrient-regulated lipid kinase required for activation of p70 S6 kinase. J Biol Chem 280:33076–33082PubMedGoogle Scholar
  16. Campbell IG, Russell SE, Choong DY, Montgomery KG, Ciavarella ML, Hooi CS, Cristiano BE, Pearson RB, Phillips WA (2004) Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res 64:7678–7681PubMedGoogle Scholar
  17. Carpenter CL, Duckworth BC, Auger KR, Cohen B, Schaffhausen BS, Cantley LC (1990) Purification and characterization of phosphoinositide 3-kinase from rat liver. J Biol Chem 265:19704–19711PubMedGoogle Scholar
  18. Chang HW, Aoki M, Fruman D, Auger KR, Bellacosa A, Tsichlis PN, Cantley LC, Roberts TM, Vogt PK (1997) Transformation of chicken cells by the gene encoding the catalytic subunit of PI 3-kinase. Science 276:1848–1850PubMedGoogle Scholar
  19. Chantry D, Vojtek A, Kashishian A, Holtzman DA, Wood C, Gray PW, Cooper JA, Hoekstra MF (1997) p110delta, a novel phosphatidylinositol 3-kinase catalytic subunit that associates with p85 and is expressed predominantly in leukocytes. J Biol Chem 272:19236–19241PubMedGoogle Scholar
  20. Cheever ML, Sato TK, de Beer T, Kutateladze TG, Emr SD, Overduin M (2001) Phox domain interaction with PtdIns(3)P targets the Vam7 t-SNARE to vacuole membranes. Nat Cell Biol 3:613–618PubMedGoogle Scholar
  21. Clayton E, Bardi G, Bell SE, Chantry D, Downes CP, Gray A, Humphries LA, Rawlings D, Reynolds H, Vigorito E, Turner M (2002) A crucial role for the p110delta subunit of phosphatidylinositol 3-kinase in B cell development and activation. J Exp Med 196:753–763PubMedGoogle Scholar
  22. Cloughesy TF, Yoshimoto K, Nghiemphu P, Brown K, Dang J, Zhu S, Hsueh T, Chen Y, Wang W, Youngkin D, Liau L, Martin N, Becker D, Bergsneider M, Lai A, Green R, Oglesby T, Koleto M, Trent J, Horvath S, Mischel PS, Mellinghoff IK, Sawyers CL (2008) Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS Med 5(1):e8PubMedGoogle Scholar
  23. 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
  24. Coloff JL, Rathmell JC (2006) Metabolic regulation of Akt: roles reversed. J Cell Biol 175:845–847PubMedGoogle Scholar
  25. Courtneidge SA, Heber A (1987) An 81 kd protein complexed with middle T antigen and pp 60c-src: a possible phosphatidylinositol kinase. Cell 50:1031–1037PubMedGoogle Scholar
  26. Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA (1995) Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature 378:785–789PubMedGoogle Scholar
  27. Dan S, Yoshimi H, Okamura M, Mukai Y, Yamori T (2009) Inhibition of PI3K by ZSTK474 suppressed tumor growth not via apoptosis but G0/G1 arrest. Biochem Biophys Res Commun 379:104–109PubMedGoogle Scholar
  28. Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91:231–241PubMedGoogle Scholar
  29. del Peso L, Gonzalez-Garcia M, Page C, Herrera R, Nunez G (1997) Interleukin-3-induced phosphorylation of BAD through the protein kinase Akt. Science 278:687–689PubMedGoogle Scholar
  30. Di Paolo G, De Camilli P (2006) Phosphoinositides in cell regulation and membrane dynamics. Nature 443:651–657PubMedGoogle Scholar
  31. Domin J, Pages F, Volinia S, Rittenhouse SE, Zvelebil MJ, Stein RC, Waterfield MD (1997) Cloning of a human phosphoinositide 3-kinase with a C2 domain that displays reduced sensitivity to the inhibitor wortmannin. Biochem J 326(Pt 1):139–147PubMedGoogle Scholar
  32. Edgar KA, Wallin JJ, Berry M, Lee LB, Prior WW, Sampath D, Friedman LS, Belvin M (2010) Isoform-specific phosphoinositide 3-kinase inhibitors exert distinct effects in solid tumors. Cancer Res 70:1164–1172PubMedGoogle Scholar
  33. Elis W, Triantafellow E, Wolters NM, Sian KR, Caponigro G, Borawski J, Gaither LA, Murphy LO, Finan PM, Mackeigan JP (2008) Down-regulation of class II phosphoinositide 3-kinase alpha expression below a critical threshold induces apoptotic cell death. Mol Cancer Res 6:614–623PubMedGoogle Scholar
  34. Ellson CD, Gobert-Gosse S, Anderson KE, Davidson K, Erdjument-Bromage H, Tempst P, Thuring JW, Cooper MA, Lim ZY, Holmes AB, Gaffney PR, Coadwell J, Chilvers ER, Hawkins PT, Stephens LR (2001) PtdIns(3)P regulates the neutrophil oxidase complex by binding to the PX domain of p40(phox). Nat Cell Biol 3:679–682PubMedGoogle Scholar
  35. Engelman JA, Chen L, Tan X, Crosby K, Guimaraes AR, Upadhyay R, Maira M, McNamara K, Perera SA, Song Y, Chirieac LR, Kaur R, Lightbown A, Simendinger J, Li T, Padera RF, Garcia-Echeverria C, Weissleder R, Mahmood U, Cantley LC, Wong KK (2008) Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med 14:1351–1356PubMedGoogle Scholar
  36. Escobedo JA, Navankasattusas S, Kavanaugh WM, Milfay D, Fried VA, Williams LT (1991) cDNA cloning of a novel 85 kd protein that has SH2 domains and regulates binding of PI3-kinase to the PDGF beta-receptor. Cell 65:75–82PubMedGoogle Scholar
  37. Faber AC, Li D, Song Y, Liang MC, Yeap BY, Bronson RT, Lifshits E, Chen Z, Maira SM, Garcia-Echeverria C, Wong KK, Engelman JA (2009) Differential induction of apoptosis in HER2 and EGFR addicted cancers following PI3K inhibition. Proc Natl Acad Sci USA 106:19503–19508PubMedGoogle Scholar
  38. Falasca M, Maffucci T (2009) Rethinking phosphatidylinositol 3-monophosphate. Biochim Biophys Acta 1793:1795–1803PubMedGoogle Scholar
  39. Fan QW, Cheng CK, Nicolaides TP, Hackett CS, Knight ZA, Shokat KM, Weiss WA (2007) A dual phosphoinositide-3-kinase alpha/mTOR inhibitor cooperates with blockade of epidermal growth factor receptor in PTEN-mutant glioma. Cancer Res 67:7960–7965PubMedGoogle Scholar
  40. Fine B, Hodakoski C, Koujak S, Su T, Saal LH, Maurer M, Hopkins B, Keniry M, Sulis ML, Mense S, Hibshoosh H, Parsons R (2009) Activation of the PI3K pathway in cancer through inhibition of PTEN by exchange factor P-REX2a. Science 325:1261–1265PubMedGoogle Scholar
  41. Flinn IA, Byrd JC, Furman RR, Brown JR, Benson DM, Coutre SE, Kahl BS, Smith BD, Wagner-Johnston ND, Spurgeon SE, Giese NA, Yu AS (2009) Evidence of clinical activity in a phase 1 study of CAL-101, an oral P110δ isoform-selective inhibitor of phosphatidylinositol 3-kinase, in patients with relapsed or refractory B-Cell malignancies. ASH 2009 AbstractGoogle Scholar
  42. 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 441:366–370PubMedGoogle Scholar
  43. Foukas LC, Berenjeno IM, Gray A, Khwaja A, Vanhaesebroeck B (2010) Activity of any class IA PI 3-kinase isoform can sustain cell proliferation and survival. Proc Natl Acad Sci USA (in press)Google Scholar
  44. Franke TF, Yang SI, Chan TO, Datta K, Kazlauskas A, Morrison DK, Kaplan DR, Tsichlis PN (1995) The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase. Cell 81:727–736PubMedGoogle Scholar
  45. Frech M, Andjelkovic M, Ingley E, Reddy KK, Falck JR, Hemmings BA (1997) High affinity binding of inositol phosphates and phosphoinositides to the pleckstrin homology domain of RAC/protein kinase B and their influence on kinase activity. J Biol Chem 272:8474–8481PubMedGoogle Scholar
  46. Fry MJ, Panayotou G, Dhand R, Ruiz-Larrea F, Gout I, Nguyen O, Courtneidge SA, Waterfield MD (1992) Purification and characterization of a phosphatidylinositol 3-kinase complex from bovine brain by using phosphopeptide affinity columns. Biochem J 288(Pt 2):383–393PubMedGoogle Scholar
  47. Gaullier JM, Simonsen A, D'Arrigo A, Bremnes B, Stenmark H, Aasland R (1998) FYVE fingers bind PtdIns(3)P. Nature 394:432–433PubMedGoogle Scholar
  48. Gewinner C, Wang ZC, Richardson A, Teruya-Feldstein J, Etemadmoghadam D, Bowtell D, Barretina J, Lin WM, Rameh L, Salmena L, Pandolfi PP, Cantley LC (2009) Evidence that inositol polyphosphate 4-phosphatase type II is a tumor suppressor that inhibits PI3K signaling. Cancer Cell 16:115–125PubMedGoogle Scholar
  49. Graupera M, Guillermet-Guibert J, Foukas LC, Phng LK, Cain RJ, Salpekar A, Pearce W, Meek S, Millan J, Cutillas PR, Smith AJ, Ridley AJ, Ruhrberg C, Gerhardt H, Vanhaesebroeck B (2008) Angiogenesis selectively requires the p110alpha isoform of PI3K to control endothelial cell migration. Nature 453:662–666PubMedGoogle Scholar
  50. Guillard S, Clarke PA, Te Poele R, Mohri Z, Bjerke L, Valenti M, Raynaud F, Eccles SA, Workman P (2009) Molecular pharmacology of phosphatidylinositol 3-kinase inhibition in human glioma. Cell Cycle 8:443–453PubMedGoogle Scholar
  51. Gymnopoulos M, Elsliger MA, Vogt PK (2007) Rare cancer-specific mutations in PIK3CA show gain of function. Proc Natl Acad Sci USA 104:5569–5574PubMedGoogle Scholar
  52. Harlan JE, Hajduk PJ, Yoon HS, Fesik SW (1994) Pleckstrin homology domains bind to phosphatidylinositol-4,5-bisphosphate. Nature 371:168–170PubMedGoogle Scholar
  53. Haslam RJ, Koide HB, Hemmings BA (1993) Pleckstrin domain homology. Nature 363:309–310PubMedGoogle Scholar
  54. Hawkins PT, Jackson TR, Stephens LR (1992) Platelet-derived growth factor stimulates synthesis of PtdIns(3,4,5)P3 by activating a PtdIns(4,5)P2 3-OH kinase. Nature 358:157–159PubMedGoogle Scholar
  55. Herman PK, Emr SD (1990) Characterization of VPS34, a gene required for vacuolar protein sorting and vacuole segregation in Saccharomyces cerevisiae. Mol Cell Biol 10:6742–6754PubMedGoogle Scholar
  56. Hiles ID, Otsu M, Volinia S, Fry MJ, Gout I, Dhand R, Panayotou G, Ruiz-Larrea F, Thompson A, Totty NF et al (1992) Phosphatidylinositol 3-kinase: structure and expression of the 110 kd catalytic subunit. Cell 70:419–429PubMedGoogle Scholar
  57. Hill K, Welti S, Yu J, Murray JT, Yip SC, Condeelis JS, Segall JE, Backer JM (2000) Specific requirement for the p85-p110alpha phosphatidylinositol 3-kinase during epidermal growth factor-stimulated actin nucleation in breast cancer cells. J Biol Chem 275:3741–3744PubMedGoogle Scholar
  58. 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 287:1049–1053PubMedGoogle Scholar
  59. Hu P, Mondino A, Skolnik EY, Schlessinger J (1993) Cloning of a novel, ubiquitously expressed human phosphatidylinositol 3-kinase and identification of its binding site on p85. Mol Cell Biol 13:7677–7688PubMedGoogle Scholar
  60. Hurley JH (2006) Membrane binding domains. Biochim Biophys Acta 1761:805–811PubMedGoogle Scholar
  61. 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
  62. Jackson TR, Stephens LR, Hawkins PT (1992) Receptor specificity of growth factor-stimulated synthesis of 3-phosphorylated inositol lipids in Swiss 3T3 cells. J Biol Chem 267:16627–16636PubMedGoogle Scholar
  63. Jackson SP, Schoenwaelder SM, Goncalves I, Nesbitt WS, Yap CL, Wright CE, Kenche V, Anderson KE, Dopheide SM, Yuan Y, Sturgeon SA, Prabaharan H, Thompson PE, Smith GD, Shepherd PR, Daniele N, Kulkarni S, Abbott B, Saylik D, Jones C, Lu L, Giuliano S, Hughan SC, Angus JA, Robertson AD, Salem HH (2005) PI 3-kinase p110beta: a new target for antithrombotic therapy. Nat Med 11:507–514PubMedGoogle Scholar
  64. Jacoby M, Cox JJ, Gayral S, Hampshire DJ, Ayub M, Blockmans M, Pernot E, Kisseleva MV, Compere P, Schiffmann SN, Gergely F, Riley JH, Perez-Morga D, Woods CG, Schurmans S (2009) INPP5E mutations cause primary cilium signaling defects, ciliary instability and ciliopathies in human and mouse. Nat Genet 41:1027–1031PubMedGoogle Scholar
  65. Jaiswal BS, Janakiraman V, Kljavin NM, Chaudhuri S, Stern HM, Wang W, Kan Z, Dbouk HA, Peters BA, Waring P, Dela Vega T, Kenski DM, Bowman KK, Lorenzo M, Li H, Wu J, Modrusan Z, Stinson J, Eby M, Yue P, Kaminker JS, de Sauvage FJ, Backer JM, Seshagiri S (2009) Somatic mutations in p85alpha promote tumorigenesis through class IA PI3K activation. Cancer Cell 16:463–474PubMedGoogle Scholar
  66. Jones RG, Thompson CB (2009) Tumor suppressors and cell metabolism: a recipe for cancer growth. Genes Dev 23:537–548PubMedGoogle Scholar
  67. 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
  68. Jou ST, Carpino N, Takahashi Y, Piekorz R, Chao JR, 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 22:8580–8591PubMedGoogle Scholar
  69. Kanai F, Liu H, Field SJ, Akbary H, Matsuo T, Brown GE, Cantley LC, Yaffe MB (2001) The PX domains of p47phox and p40phox bind to lipid products of PI(3)K. Nat Cell Biol 3:675–678PubMedGoogle Scholar
  70. Kaplan DR, Whitman M, Schaffhausen B, Pallas DC, White M, Cantley L, Roberts TM (1987) Common elements in growth factor stimulation and oncogenic transformation: 85 kd phosphoprotein and phosphatidylinositol kinase activity. Cell 50:1021–1029PubMedGoogle Scholar
  71. Klarlund JK, Guilherme A, Holik JJ, Virbasius JV, Chawla A, Czech MP (1997) Signaling by phosphoinositide-3,4,5-trisphosphate through proteins containing pleckstrin and Sec7 homology domains. Science 275:1927–1930PubMedGoogle Scholar
  72. Kops GJ, de Ruiter ND, De Vries-Smits AM, Powell DR, Bos JL, Burgering BM (1999) Direct control of the Forkhead transcription factor AFX by protein kinase B. Nature 398:630–634PubMedGoogle Scholar
  73. Krugmann S, Anderson KE, Ridley SH, Risso N, McGregor A, Coadwell J, Davidson K, Eguinoa A, Ellson CD, Lipp P, Manifava M, Ktistakis N, Painter G, Thuring JW, Cooper MA, Lim ZY, Holmes AB, Dove SK, Michell RH, Grewal A, Nazarian A, Erdjument-Bromage H, Tempst P, Stephens LR, Hawkins PT (2002) Identification of ARAP3, a novel PI3K effector regulating both Arf and Rho GTPases, by selective capture on phosphoinositide affinity matrices. Mol Cell 9:95–108PubMedGoogle Scholar
  74. Leevers SJ, Weinkove D, MacDougall LK, Hafen E, Waterfield MD (1996) The Drosophila phosphoinositide 3-kinase Dp110 promotes cell growth. EMBO J 15:6584–6594PubMedGoogle Scholar
  75. Lemmon MA (2008) Membrane recognition by phospholipid-binding domains. Nat Rev Mol Cell Biol 9:99–111PubMedGoogle Scholar
  76. 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 287:1046–1049PubMedGoogle Scholar
  77. Macara IG, Marinetti GV, Balduzzi PC (1984) Transforming protein of avian sarcoma virus UR2 is associated with phosphatidylinositol kinase activity: possible role in tumorigenesis. Proc Natl Acad Sci USA 81:2728–2732PubMedGoogle Scholar
  78. MacDougall LK, Domin J, Waterfield MD (1995) A family of phosphoinositide 3-kinases in Drosophila identifies a new mediator of signal transduction. Curr Biol 5:1404–1415PubMedGoogle Scholar
  79. Maehama T, Dixon JE (1998) The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 273:13375–13378PubMedGoogle Scholar
  80. Mandelker D, Gabelli SB, Schmidt-Kittler O, Zhu J, Cheong I, Huang CH, Kinzler KW, Vogelstein B, Amzel LM (2009) A frequent kinase domain mutation that changes the interaction between PI3Kalpha and the membrane. Proc Natl Acad Sci USA 106:16996–17001PubMedGoogle Scholar
  81. Mayer BJ, Ren R, Clark KL, Baltimore D (1993) A putative modular domain present in diverse signaling proteins. Cell 73:629–630PubMedGoogle Scholar
  82. Miled N, Yan Y, Hon WC, Perisic O, Zvelebil M, Inbar Y, Schneidman-Duhovny D, Wolfson HJ, Backer JM, Williams RL (2007) Mechanism of two classes of cancer mutations in the phosphoinositide 3-kinase catalytic subunit. Science 317:239–242PubMedGoogle Scholar
  83. Misawa H, Ohtsubo M, Copeland NG, Gilbert DJ, Jenkins NA, Yoshimura A (1998) Cloning and characterization of a novel class II phosphoinositide 3-kinase containing C2 domain. Biochem Biophys Res Commun 244:531–539PubMedGoogle Scholar
  84. Morgan SJ, Smith AD, Parker PJ (1990) Purification and characterization of bovine brain type I phosphatidylinositol kinase. Eur J Biochem 191:761–767PubMedGoogle Scholar
  85. Morris JZ, Tissenbaum HA, Ruvkun G (1996) A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans. Nature 382:536–539PubMedGoogle Scholar
  86. 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 579:5123–5128PubMedGoogle Scholar
  87. Mu FT, Callaghan JM, Steele-Mortimer O, Stenmark H, Parton RG, Campbell PL, McCluskey J, Yeo JP, Tock EP, Toh BH (1995) EEA1, an early endosome-associated protein. EEA1 is a conserved alpha-helical peripheral membrane protein flanked by cysteine “fingers” and contains a calmodulin-binding IQ motif. J Biol Chem 270:13503–13511PubMedGoogle Scholar
  88. Nicot AS, Laporte J (2008) Endosomal phosphoinositides and human diseases. Traffic 9:1240–1249PubMedGoogle Scholar
  89. Nobukuni T, Joaquin M, Roccio M, Dann SG, Kim SY, Gulati P, Byfield MP, Backer JM, Natt F, Bos JL, Zwartkruis FJ, Thomas G (2005) Amino acids mediate mTOR/raptor signaling through activation of class 3 phosphatidylinositol 3OH-kinase. Proc Natl Acad Sci USA 102:14238–14243PubMedGoogle Scholar
  90. O'Brien C, Wallin JJ, Sampath D, Guhathakurta D, Savage H, Punnoose EA, Guan J, Berry L, Prior WW, Amler LC, Belvin M, Friedman L, Lackner M (2010) Predictive biomarkers of sensitivity to the phosphatidylinositol 3′ kinase inhibitor GDC-0941 in breast cancer preclinical models. Clin Cancer Res [Epub ahead of print]Google Scholar
  91. Ogg S, Paradis S, Gottlieb S, Patterson GI, Lee L, Tissenbaum HA, Ruvkun G (1997) The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature 389:994–999PubMedGoogle Scholar
  92. 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
  93. Okkenhaug K, Bilancio A, Farjot G, Priddle H, Sancho S, Peskett E, Pearce W, Meek SE, Salpekar A, Waterfield MD, Smith AJ, Vanhaesebroeck B (2002) Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. Science 297:1031–1034PubMedGoogle Scholar
  94. Ono F, Nakagawa T, Saito S, Owada Y, Sakagami H, Goto K, Suzuki M, Matsuno S, Kondo H (1998) A novel class II phosphoinositide 3-kinase predominantly expressed in the liver and its enhanced expression during liver regeneration. J Biol Chem 273:7731–7736PubMedGoogle Scholar
  95. Ooms LM, Horan KA, Rahman P, Seaton G, Gurung R, Kethesparan DS, Mitchell CA (2009) The role of the inositol polyphosphate 5-phosphatases in cellular function and human disease. Biochem J 419:29–49PubMedGoogle Scholar
  96. Otsu M, Hiles I, Gout I, Fry MJ, Ruiz-Larrea F, Panayotou G, Thompson A, Dhand R, Hsuan J, Totty N et al (1991) Characterization of two 85 kd proteins that associate with receptor tyrosine kinases, middle-T/pp 60c-src complexes, and PI3-kinase. Cell 65:91–104PubMedGoogle Scholar
  97. Pang H, Flinn R, Patsialou A, Wyckoff J, Roussos ET, Wu H, Pozzuto M, Goswami S, Condeelis JS, Bresnick AR, Segall JE, Backer JM (2009) Differential enhancement of breast cancer cell motility and metastasis by helical and kinase domain mutations of class IA phosphoinositide 3-kinase. Cancer Res 69:8868–8876PubMedGoogle Scholar
  98. Papakonstanti EA, Ridley AJ, Vanhaesebroeck B (2007) The p110delta isoform of PI 3-kinase negatively controls RhoA and PTEN. EMBO J 26:3050–3061PubMedGoogle Scholar
  99. Papakonstanti EA, Zwaenepoel O, Bilancio A, Burns E, Nock GE, Houseman B, Shokat K, Ridley AJ, Vanhaesebroeck B (2008) Distinct roles of class IA PI3K isoforms in primary and immortalised macrophages. J Cell Sci 121:4124–4133PubMedGoogle Scholar
  100. Paradis S, Ruvkun G (1998) Caenorhabditis elegans Akt/PKB transduces insulin receptor-like signals from AGE-1 PI3 kinase to the DAF-16 transcription factor. Genes Dev 12:2488–2498PubMedGoogle Scholar
  101. Parsons DW, Jones S, Zhang X, Lin JC, Leary RJ, Angenendt P, Mankoo P, Carter H, Siu IM, Gallia GL, Olivi A, McLendon R, Rasheed BA, Keir S, Nikolskaya T, Nikolsky Y, Busam DA, Tekleab H, Diaz LA Jr, Hartigan J, Smith DR, Strausberg RL, Marie SK, Shinjo SM, Yan H, Riggins GJ, Bigner DD, Karchin R, Papadopoulos N, Parmigiani G, Vogelstein B, Velculescu VE, Kinzler KW (2008) An integrated genomic analysis of human glioblastoma multiforme. Science 321:1807–1812PubMedGoogle Scholar
  102. 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
  103. Plas DR, Thompson CB (2005) Akt-dependent transformation: there is more to growth than just surviving. Oncogene 24:7435–7442PubMedGoogle Scholar
  104. Powis G, Bonjouklian R, Berggren MM, Gallegos A, Abraham R, Ashendel C, Zalkow L, Matter WF, Dodge J, Grindey G et al (1994) Wortmannin, a potent and selective inhibitor of phosphatidylinositol-3-kinase. Cancer Res 54:2419–2423PubMedGoogle Scholar
  105. Raynaud FI, Eccles S, Clarke PA, Hayes A, Nutley B, Alix S, Henley A, Di-Stefano F, Ahmad Z, Guillard S, Bjerke LM, Kelland L, Valenti M, Patterson L, Gowan S, de Haven BA, Hayakawa M, Kaizawa H, Koizumi T, Ohishi T, Patel S, Saghir N, Parker P, Waterfield M, Workman P (2007) Pharmacologic characterization of a potent inhibitor of class I phosphatidylinositide 3-kinases. Cancer Res 67:5840–5850PubMedGoogle Scholar
  106. Roche S, Koegl M, Courtneidge SA (1994) The phosphatidylinositol 3-kinase alpha is required for DNA synthesis induced by some, but not all, growth factors. Proc Natl Acad Sci USA 91:9185–9189PubMedGoogle Scholar
  107. Roche S, Downward J, Raynal P, Courtneidge SA (1998) A function for phosphatidylinositol 3-kinase beta (p85alpha-p110beta) in fibroblasts during mitogenesis: requirement for insulin- and lysophosphatidic acid-mediated signal transduction. Mol Cell Biol 18:7119–7129PubMedGoogle Scholar
  108. Rodriguez-Viciana P, Warne PH, Dhand R, Vanhaesebroeck B, Gout I, Fry MJ, Waterfield MD, Downward J (1994) Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 370:527–532PubMedGoogle Scholar
  109. 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 7:191–201PubMedGoogle Scholar
  110. Ruckle T, Schwarz MK, Rommel C (2006) PI3Kgamma inhibition: towards an ‘aspirin of the 21st century’? Nat Rev Drug Discov 5:903–918PubMedGoogle Scholar
  111. 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
  112. 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
  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. Sasaki T, Irie-Sasaki J, Jones RG, Oliveira-dos-Santos AJ, Stanford WL, Bolon B, Wakeham A, Itie A, Bouchard D, Kozieradzki I, Joza N, Mak TW, Ohashi PS, Suzuki A, Penninger JM (2000) Function of PI3Kgamma in thymocyte development, T cell activation, and neutrophil migration. Science 287:1040–1046PubMedGoogle Scholar
  115. Schu PV, Takegawa K, Fry MJ, Stack JH, Waterfield MD, Emr SD (1993) Phosphatidylinositol 3-kinase encoded by yeast VPS34 gene essential for protein sorting. Science 260:88–91PubMedGoogle Scholar
  116. Sergina NV, Rausch M, Wang D, Blair J, Hann B, Shokat KM, Moasser MM (2007) Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature 445:437–441PubMedGoogle Scholar
  117. Shibasaki F, Homma Y, Takenawa T (1991) Two types of phosphatidylinositol 3-kinase from bovine thymus. Monomer and heterodimer form. J Biol Chem 266:8108–8114PubMedGoogle Scholar
  118. Shuttleworth S, Silva F, Tomassi C, Cecil A, Hill T, Rogers H, Townsend P (2009) Progress in the design and development of phosphoinositide 3-kinase (PI3K) inhibitors for the treatment of chronic diseases. Prog Med Chem 48:81–131PubMedGoogle Scholar
  119. Sjolander A, Yamamoto K, Huber BE, Lapetina EG (1991) Association of p21ras with phosphatidylinositol 3-kinase. Proc Natl Acad Sci USA 88:7908–7912PubMedGoogle Scholar
  120. Skolnik EY, Margolis B, Mohammadi M, Lowenstein E, Fischer R, Drepps A, Ullrich A, Schlessinger J (1991) Cloning of PI3 kinase-associated p85 utilizing a novel method for expression/cloning of target proteins for receptor tyrosine kinases. Cell 65:83–90PubMedGoogle Scholar
  121. Song X, Xu W, Zhang A, Huang G, Liang X, Virbasius JV, Czech MP, Zhou GW (2001) Phox homology domains specifically bind phosphatidylinositol phosphates. Biochemistry 40:8940–8944PubMedGoogle Scholar
  122. Soond DR, Bjorgo E, Moltu K, Dale VQ, Patton DT, Torgersen KM, Galleway F, Twomey B, Clark J, Gaston JH, Tasken K, Bunyard P, Okkenhaug K (2010) PI3K p110{delta} regulates T cell cytokine production during primary and secondary immune responses in mice and humans. Blood 115:2203–2213PubMedGoogle Scholar
  123. Sos ML, Fischer S, Ullrich R, Peifer M, Heuckmann JM, Koker M, Heynck S, Stuckrath I, Weiss J, Fischer F, Michel K, Goel A, Regales L, Politi KA, Perera S, Getlik M, Heukamp LC, Ansen S, Zander T, Beroukhim R, Kashkar H, Shokat KM, Sellers WR, Rauh D, Orr C, Hoeflich KP, Friedman L, Wong KK, Pao W, Thomas RK (2009) Identifying genotype-dependent efficacy of single and combined PI3K- and MAPK-pathway inhibition in cancer. Proc Natl Acad Sci USA 106:18351–18356PubMedGoogle Scholar
  124. Stemke-Hale K, Gonzalez-Angulo AM, Lluch A, Neve RM, Kuo WL, Davies M, Carey M, Hu Z, Guan Y, Sahin A, Symmans WF, Pusztai L, Nolden LK, Horlings H, Berns K, Hung MC, van de Vijver MJ, Valero V, Gray JW, Bernards R, Mills GB, Hennessy BT (2008) An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res 68:6084–6091PubMedGoogle Scholar
  125. Stenmark H, Aasland R, Toh BH, D'Arrigo A (1996) Endosomal localization of the autoantigen EEA1 is mediated by a zinc-binding FYVE finger. J Biol Chem 271:24048–24054PubMedGoogle Scholar
  126. Stephens L, Smrcka A, Cooke FT, Jackson TR, Sternweis PC, Hawkins PT (1994) A novel phosphoinositide 3 kinase activity in myeloid-derived cells is activated by G protein beta gamma subunits. Cell 77:83–93PubMedGoogle Scholar
  127. Stephens LR, Eguinoa A, Erdjument-Bromage H, Lui M, Cooke F, Coadwell J, Smrcka AS, Thelen M, Cadwallader K, Tempst P, Hawkins PT (1997) The G beta gamma sensitivity of a PI3K is dependent upon a tightly associated adaptor, p101. Cell 89:105–114PubMedGoogle Scholar
  128. 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
  129. Stocker H, Andjelkovic M, Oldham S, Laffargue M, Wymann MP, Hemmings BA, Hafen E (2002) Living with lethal PIP3 levels: viability of flies lacking PTEN restored by a PH domain mutation in Akt/PKB. Science 295:2088–2091PubMedGoogle Scholar
  130. 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
  131. Stoyanov B, Volinia S, Hanck T, Rubio I, Loubtchenkov M, Malek D, Stoyanova S, Vanhaesebroeck B, Dhand R, Nurnberg B et al (1995) Cloning and characterization of a G protein-activated human phosphoinositide-3 kinase. Science 269:690–693PubMedGoogle Scholar
  132. Sugimoto Y, Whitman M, Cantley LC, Erikson RL (1984) Evidence that the Rous sarcoma virus transforming gene product phosphorylates phosphatidylinositol and diacylglycerol. Proc Natl Acad Sci USA 81:2117–2121PubMedGoogle Scholar
  133. TGCA (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061–1068Google Scholar
  134. Thomas RK, Baker AC, Debiasi RM, Winckler W, Laframboise T, Lin WM, Wang M, Feng W, Zander T, MacConaill L, Lee JC, Nicoletti R, Hatton C, Goyette M, Girard L, Majmudar K, Ziaugra L, Wong KK, Gabriel S, Beroukhim R, Peyton M, Barretina J, Dutt A, Emery C, Greulich H, Shah K, Sasaki H, Gazdar A, Minna J, Armstrong SA, Mellinghoff IK, Hodi FS, Dranoff G, Mischel PS, Cloughesy TF, Nelson SF, Liau LM, Mertz K, Rubin MA, Moch H, Loda M, Catalona W, Fletcher J, Signoretti S, Kaye F, Anderson KC, Demetri GD, Dummer R, Wagner S, Herlyn M, Sellers WR, Meyerson M, Garraway LA (2007) High-throughput oncogene mutation profiling in human cancer. Nat Genet 39:347–351PubMedGoogle Scholar
  135. Traynor-Kaplan AE, Harris AL, Thompson BL, Taylor P, Sklar LA (1988) An inositol tetrakisphosphate-containing phospholipid in activated neutrophils. Nature 334:353–356PubMedGoogle Scholar
  136. Traynor-Kaplan AE, Thompson BL, Harris AL, Taylor P, Omann GM, Sklar LA (1989) Transient increase in phosphatidylinositol 3,4-bisphosphate and phosphatidylinositol trisphosphate during activation of human neutrophils. J Biol Chem 264:15668–15673PubMedGoogle Scholar
  137. Vanhaesebroeck B, Leevers SJ, Panayotou G, Waterfield MD (1997a) Phosphoinositide 3-kinases: a conserved family of signal transducers. Trends Biochem Sci 22:267–272PubMedGoogle Scholar
  138. Vanhaesebroeck B, Welham MJ, Kotani K, Stein R, Warne PH, Zvelebil MJ, Higashi K, Volinia S, Downward J, Waterfield MD (1997b) P110delta, a novel phosphoinositide 3-kinase in leukocytes. Proc Natl Acad Sci USA 94:4330–4335PubMedGoogle Scholar
  139. Vanhaesebroeck B, Jones GE, Allen WE, Zicha D, Hooshmand-Rad R, Sawyer C, Wells C, Waterfield MD, Ridley AJ (1999) Distinct PI(3)Ks mediate mitogenic signalling and cell migration in macrophages. Nat Cell Biol 1:69–71PubMedGoogle Scholar
  140. Vanhaesebroeck B, Leevers SJ, Ahmadi K, Timms J, Katso R, Driscoll PC, Woscholski R, Parker PJ, Waterfield MD (2001) Synthesis and function of 3-phosphorylated inositol lipids. Annu Rev Biochem 70:535–602PubMedGoogle Scholar
  141. Vanhaesebroeck B, Guillermet-Guibert J, Graupera M, Bilanges B (2010) The emerging mechanisms of isoform-specific PI3K signalling. Nat Rev Mol Cell Biol (in press)Google Scholar
  142. 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
  143. Virbasius JV, Guilherme A, Czech MP (1996) Mouse p170 is a novel phosphatidylinositol 3-kinase containing a C2 domain. J Biol Chem 271:13304–13307PubMedGoogle Scholar
  144. Vlahos CJ, Matter WF, Hui KY, Brown RF (1994) A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J Biol Chem 269:5241–5248PubMedGoogle Scholar
  145. Walker EH, Perisic O, Ried C, Stephens L, Williams RL (1999) Structural insights into phosphoinositide 3-kinase catalysis and signalling. Nature 402:313–320PubMedGoogle Scholar
  146. Welch HC, Coadwell WJ, Ellson CD, Ferguson GJ, Andrews SR, Erdjument-Bromage H, Tempst P, Hawkins PT, Stephens LR (2002) P-Rex1, a PtdIns(3,4,5)P3- and Gbetagamma-regulated guanine-nucleotide exchange factor for Rac. Cell 108:809–821PubMedGoogle Scholar
  147. Whitman M, Kaplan DR, Schaffhausen B, Cantley L, Roberts TM (1985) Association of phosphatidylinositol kinase activity with polyoma middle-T competent for transformation. Nature 315:239–242PubMedGoogle Scholar
  148. Whitman M, Downes CP, Keeler M, Keller T, Cantley L (1988) Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate. Nature 332:644–646PubMedGoogle Scholar
  149. Wood LD, Parsons DW, Jones S, Lin J, Sjoblom T, Leary RJ, Shen D, Boca SM, Barber T, Ptak J, Silliman N, Szabo S, Dezso Z, Ustyanksky V, Nikolskaya T, Nikolsky Y, Karchin R, Wilson PA, Kaminker JS, Zhang Z, Croshaw R, Willis J, Dawson D, Shipitsin M, Willson JK, Sukumar S, Polyak K, Park BH, Pethiyagoda CL, Pant PV, Ballinger DG, Sparks AB, Hartigan J, Smith DR, Suh E, Papadopoulos N, Buckhaults P, Markowitz SD, Parmigiani G, Kinzler KW, Velculescu VE, Vogelstein B (2007) The genomic landscapes of human breast and colorectal cancers. Science 318:1108–1113PubMedGoogle Scholar
  150. Xu Y, Hortsman H, Seet L, Wong SH, Hong W (2001) SNX3 regulates endosomal function through its PX-domain-mediated interaction with PtdIns(3)P. Nat Cell Biol 3:658–666PubMedGoogle Scholar
  151. Yano H, Nakanishi S, Kimura K, Hanai N, Saitoh Y, Fukui Y, Nonomura Y, Matsuda Y (1993) Inhibition of histamine secretion by wortmannin through the blockade of phosphatidylinositol 3-kinase in RBL-2H3 cells. J Biol Chem 268:25846–25856PubMedGoogle Scholar
  152. Yao R, Cooper GM (1995) Requirement for phosphatidylinositol-3 kinase in the prevention of apoptosis by nerve growth factor. Science 267:2003–2006PubMedGoogle Scholar
  153. Zhou K, Takegawa K, Emr SD, Firtel RA (1995) A phosphatidylinositol (PI) kinase gene family in Dictyostelium discoideum: biological roles of putative mammalian p110 and yeast Vps34p PI 3-kinase homologs during growth and development. Mol Cell Biol 15:5645–5656PubMedGoogle Scholar
  154. Zvelebil MJ, MacDougall L, Leevers S, Volinia S, Vanhaesebroeck B, Gout I, Panayotou G, Domin J, Stein R, Pages F et al (1996) Structural and functional diversity of phosphoinositide 3-kinases. Philos Trans R Soc Lond B Biol Sci 351:217–223PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  • Bart Vanhaesebroeck
    • 1
  • Peter K. Vogt
    • 2
  • Christian Rommel
    • 3
  1. 1.Centre for Cell Signalling, Institute of Cancer, Queen MaryUniversity of LondonLondonUK
  2. 2.Department of Molecular and Experimental MedicineThe Scripps Research InstituteLa JollaUSA
  3. 3.Intellikine Inc.La JollaUSA

Personalised recommendations