Skip to main content
SpringerLink
Log in

PI3-Kinases

Role in Signal Transduction

  • Chapter
Book cover Signaling Networks and Cell Cycle Control

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

  • 284 Accesses

Abstract

The membrane lipid phosphatidylinositol (PtdIns) possesses a head group with five free hydroxyl groups (Fig. 1A). Reversible phosphorylation of the hydroxyl moieties generates a family of Ptdlns derivatives known as phosphoinositides. The PI3K family of enzymes phosphorylates the 3’ hydroxyl group of PtdIns, PtdIns 4-phosphate (PtdIns4-P) and PtdIns 4,5-bisphosphate (PtdIns-4,5-P2), resulting in the formation of PtdIns 3-phosphate (PtdIns-3-P), PtdIns 3,4-bisphosphate (PtdIns-3,4-P2), and PtdIns 3,4,5trisphosphate (PtdIns-3,4,5-P3), respectively. Three PI3K classes have been defined on the basis of substrate preference and sequence homology (1) Class I PI3Ks appear to be selective for PtdIns-4,5-P2 in vivo, but can also use PtdIns-4-P and PtdIns in vitro. Class II PI3Ks preferentially phosphorylate PtdIns and PtdIns-4-P, whereas Class III enzymes use only PtdIns. PtdIns-3-P can also be phosphorylated further by another group of enzymes, the PtdInsP kinases, to produce PtdIns-3,4-P2 and PtdIns-3,5-P2 (2,3). Thus, PI3Ks are either directly or indirectly involved in the production of four phosphoinositides: PtdIns-3-P, PtdIns-3,4-P2, PtdIns-3,5-P2, and PtdIns-3,4,5-P3. Yeast contain only the class III enzyme (vps34), whereas higher eukaryotes express all three classes of PI3K.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Domin J, Waterfield MD. Using structure to define the function of phosphoinositide 3-kinase family members. FEBS Lett 1997; 410: 91–95.

    Article  PubMed  CAS  Google Scholar 

  2. Zhang X, Loijens JC, Boronenkov IV, Parker GJ, Norris FA, Chen J, Thum O, Prestwich GD, Majerus PW, Anderson RA. Phosphatidylinositol-4-phosphate 5-kinase isozymes catalyze the synthesis of 3-phosphate-containing phosphatidylinositol signaling molecules. J Biol Chem 1997; 272:17, 756–17, 761.

    Google Scholar 

  3. Rameh L, Tolias K, Duckworth B, Cantley L. A novel pathway for synthesis of PtdIns4,5-bisphosphate. Nature 1997; 390: 192–196.

    Article  PubMed  CAS  Google Scholar 

  4. Serunian LA, Haber MT, Fukui T, Kim JW, Rhee SG, Lowenstein JM, Cantley LC. Polyphosphoinositides produced by phosphatidylinositol 3-kinase are poor substrates for phospholipases C from rat liver and bovine brain. J Biol Chem 1989; 264:17, 80917, 815.

    Google Scholar 

  5. Duckworth BC, Cantley LC. PI 3-kinase and receptor-linked signal transduction, in Handbook of Lipid Research: Lipid Second Messengers (Bell RM, Exton JH, eds). Plenum Press, New York, pp 125–175.

    Google Scholar 

  6. Vanhaesebroeck B, Leevers SJ, Panayotou G, Waterfield MD. Phosphoinositide 3-kinases: A conserved family of signal transducers. Trends Biochem Sci 1997; 22: 267–272.

    Article  PubMed  CAS  Google Scholar 

  7. Fruman DA, Meyers RE, Cantley LC. Phosphoinositide kinases. Annu Rev Biochem 1998; 67: 481–507.

    Article  PubMed  CAS  Google Scholar 

  8. Carpenter CL, Duckworth BC, Auger KR, Cohen B, Schaffhausen BS, Cantley LC. Purification and characterization of phosphoinositide 3-kinase from rat liver. J Biol Chem 1990; 265:19, 704–19, 711.

    Google Scholar 

  9. Otsu M, Hiles I, Gout I, Fry M.1, Ruiz-Larrea F, Panayotou G, Thompson A, Dhand R, Hsuan J, Totty N, Smith AD, Morgan SJ, Courtneidge SA, Parker PJ, Waterfield MJ. Characterization of two 85 kd proteins that associate with receptor tyrosine kinases, middle T/pp60c-src complexes, and PI 3-kinase. Cell 1991; 65: 91–104.

    Article  PubMed  CAS  Google Scholar 

  10. Escobedo JA, Navankasattusas S, Kavanaugh WM, Milfay D, Fried VA, Williams LT. cDNA cloning of a novel 85 kd protein that has SH2 domains and regulates binding of PI3-kinase to the PDGF beta-receptor. Cell 1991; 65: 75–82.

    Article  PubMed  CAS  Google Scholar 

  11. Skolnik EY, Margolis B, Mohammadi M, Lowenstein E, Fischer R, Drepps A, Ullrich A, Schlessinger J. Cloning of PI3 kinase-associated p85 utilizing a novel method for expression/cloning of target proteins for receptor tyrosine kinases. Cell 1991; 65: 83–90.

    Article  PubMed  CAS  Google Scholar 

  12. Hiles ID, Otsu M, Volinia S, Fry MJ, Gout I, Dhand R, Panayotou G, Ruiz LF, Thompson A, Totty NF, et al. Phosphatidylinositol 3-kinase: Structure and expression of the 110 kd catalytic subunit. Cell 1992; 70: 419–429.

    Article  PubMed  CAS  Google Scholar 

  13. Stoyanov B, Volinia S, Hanck T, Rubio I, Loubtchenkov M, Malek D, Stoyanova S, Vanhaesebroeck B, Dhand R, Nurnberg B, et al. Cloning and characterization of a G protein-activated human phosphoinositide-3 kinase. Science 1995; 269: 690–693.

    Article  PubMed  CAS  Google Scholar 

  14. Stephens LR, Eguinoa A, Erdjument-Bromage H, Lui M, Cooke F, Coadwell J, Smrcka AS, Thelen M, Cadwallader K, Tempst P, Hawkins PT. The G beta gamma sensitivity of a PI3K is dependent upon a tightly associated adaptor, p101. Cell 1997; 89: 105–114.

    Article  PubMed  CAS  Google Scholar 

  15. Zhou S, Shoelson SE, Chaudhuri M, Gish G, Pawson T, Haser WG, King F, Roberts T, Ratnofsky S, Lechleider RJ, et al. SH2 domains recognize specific phosphopeptide sequences. Cell 1993; 72: 767–778.

    Article  Google Scholar 

  16. Backer JM, Myers MJ, Shoelson SE, Chin DJ, Sun XJ, Miralpeix M, Hu P, Margolis B, Skolnik EY, Schlessinger J, et al. Phosphatidylinositol 3’-kinase is activated by association with IRS-1 during insulin stimulation. EMBO J 1992; 11: 3469–3479.

    PubMed  CAS  Google Scholar 

  17. Carpenter CL, Auger KR, Chanudhuri M, Yoakim M, Schaffhausen B, Shoelson S, Cantley LC. Phosphoinositide 3-kinase is activated by phosphopeptides that bind to the SH2 domains of the 85-kDa subunit. J Biol Chem 1993; 268: 9478–9483.

    PubMed  CAS  Google Scholar 

  18. Pleiman CM, Hertz WM, Cambier JC. Activation of phosphatidylinositol-3’ kinase by Src-family kinase SH3 binding to the p85 subunit. Science 1994; 63: 1609–1612.

    Article  Google Scholar 

  19. Rodriguez VP, Warne PH, Dhand R, Vanhaesebroeck B, Gout I, Fry MJ, Waterfield MD, Downward J. Phosphatidylinositol-3-OH kinase as a direct target of Ras. Nature 1994; 370: 527–532.

    Article  Google Scholar 

  20. Rodriguez-Viciana P, Warne PH, Vanhaesebroeck B, Waterfield MD, Downward J. Activation of phosphoinositide 3-kinase by interaction with Ras and by point mutation. EMBO J 1996; 15: 2442–2451.

    PubMed  CAS  Google Scholar 

  21. Rodriguez-Viciana P, Marte BM, Warne PH, Downward J. Phosphatidylinositol 3’ kinase: One of the effectors of Ras. Philos Trans R Soc Lond Biol Sci 1996; 351: 225–231.

    Article  CAS  Google Scholar 

  22. Stephens L, Smrcka A, Cooke FT, Jackson TR, Sternweis PC, Hawkins PT. A novel phosphoinositide 3 kinase activity in myeloid-derived cells is activated by G protein beta gamma subunits. Cell 1994; 77: 83–93.

    Article  PubMed  CAS  Google Scholar 

  23. Tang X, Downes CP. Purification and characterization of Gbetagamma-responsive phosphoinositide 3-kinases from pig platelet cytosol. J Biol Chem 1997; 272:14, 19314, 199.

    Google Scholar 

  24. Kurosu H, Maehama T, Okada T, Yamamoto T, Hoshino S, Fukui Y, Ui M, Hazeki O, Katada T. Heterodimeric phosphoinositide 3-kinase consisting of p85 and pl10beta is synergistically activated by the betagamma subunits of G proteins and phosphotyrosyl peptide. J Biol Chem 1997; 272:24, 252–24, 256.

    Google Scholar 

  25. Rubio I, Rodriguez-Viciana P, Downward J, Wetzker R. Interaction of Ras with phosphoinositide 3-kinase gamma. Biochem J 1997; 326: 891–895.

    PubMed  CAS  Google Scholar 

  26. Molz L, Chen Y-W, Hirano M, Williams LT. Cpk is a novel class of Drosophila Ptdlns 3-kinase containing a C2 domain. J Biol Chem 1996; 271:13, 892–13, 899.

    Google Scholar 

  27. Stack JH, Herman PK, Schu PV, Emr SD. A membrane-associated complex containing the Vps15 protein kinase and the Vps34 PI 3-kinase is essential for protein sorting to the yeast lysosome-like vacuole. EMBO J 1993; 12: 2195–2204.

    PubMed  CAS  Google Scholar 

  28. Panaretou C, Domin J, Cockcroft S, Waterfield MD. Characterization of p150, an adaptor protein for the human phosphatidylinositol (Ptdlns) 3-kinase. Substrate presentation by phosphatidylinositol transfer protein to the p150.Ptdins 3-kinase complex. J Biol Chem 1997; 272: 2477–2485.

    Article  PubMed  CAS  Google Scholar 

  29. Stephens LR, Hughes KT, Irvine RF. Pathway of phosphatidylinositol(3,4,5)-trisphosphate synthesis in activated neutrophils. Nature 1991; 351: 33–39.

    Article  PubMed  CAS  Google Scholar 

  30. Toker A, Bachelot C, Chen C-S, Falck JR, Hartwig JH, Cantley LC, Kovacsovics T. Phosphorylation of the p47 platelet phosphoprotein is mediated by the lipid products of phosphoinositide 3-kinase. J Biol Chem 1995; 270:29, 525–29, 531.

    Google Scholar 

  31. Lemmon MA, Ferguson KM, Schlessinger J. PH domains: Diverse sequences with a common fold recruit signaling molecules to the cell surface. Cell 1996; 85: 621–624.

    Article  PubMed  CAS  Google Scholar 

  32. Rameh LE, Arvidsson A, Carraway KLR, Couvillon AD, Rathbun G, Crompton A, VanRenterghem B, Czech MP, Ravichandran KS, Burakoff SJ, Wang DS, Chen CS, Cantley LC. A comparative analysis of the phosphoinositide binding specificity of pleckstrin homology domains. J Biol Chem 1997; 272:22,059–22,066.

    Google Scholar 

  33. Touhara K, Inglese J, Pitcher JA, Shaw G, Lefkowitz RJ. Binding of G protein beta gamma-subunits to pleckstrin homology domains. J Biol Chem 1994; 269:10, 21710, 220.

    Google Scholar 

  34. Franke TF, Yang SI, Chan TO, Datta K, Kazlauskas A, Morrison DK, Kaplan DR, Tsichlis PN. The protein kinase encoded by the Akt proto-oncogene is a target of the PDGFactivated phosphatidylinositol 3-kinase. Cell 1995; 81: 727–736.

    Article  PubMed  CAS  Google Scholar 

  35. Burgering BM, Coffer PJ. Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature 1995; 376: 599–602.

    Article  PubMed  CAS  Google Scholar 

  36. Klippel A, Reinhard C, Kavanaugh WM, Apell G, Escobedo MA, Williams LT. Membrane localization of phosphatidylinositol 3-kinase is sufficient to activate multiple signal-transducing kinase pathways. Mol Cell Biol 1996; 16: 4117–4127.

    PubMed  CAS  Google Scholar 

  37. Franke TF, Kaplan DR, Cantley LC, Toker A. Direct regulation of the Akt proto-oncogene product by phosphatidylinositol-3,4-bisphosphate. Science 1997; 275: 665–668.

    Article  PubMed  CAS  Google Scholar 

  38. Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P, Hemmings BA. Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J 1996; 15: 6541–6551.

    PubMed  CAS  Google Scholar 

  39. Franke TF, Kaplan DR, Cantley LC. PI3K: Downstream AKTion blocks apoptosis. Cell 1997; 88: 435–437.

    Article  PubMed  CAS  Google Scholar 

  40. Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB, Cohen P. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol 1997; 7: 261–269.

    Article  PubMed  CAS  Google Scholar 

  41. Stokoe D, Stephens LR, Copeland T, Gaffney PR, Reese CB, Painter GF, Holmes AB, McCormick F, Hawkins PT. Dual role of phosphatidylinosito1–3,4,5-trisphosphate in the activation of protein kinase B. Science 1997; 277: 567–570.

    Article  PubMed  CAS  Google Scholar 

  42. Alessi DR, Deak M, Casamayor A, Caudwell FB, Morrice N, Norman DG, Gaffney P, Reese CB, MacDougall CN, Harbison D, Ashworth A, Bownes M. 3-phosphoinositidedependent protein kinase-1 (PDK1): structural and functional homology with the Drosophila DSTPK61 kinase. Curr Biol 1997; 7: 776–789.

    Article  PubMed  CAS  Google Scholar 

  43. Stephens L, Anderson K, Stokoe D, Erdjument-Bromage H, Painter GF, Holmes AB, Gaffney P R J, Reese CB, McCormick F, Tempst P, Coadwell J, Hawkins PT. Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B. Science 1998; 279: 710–714.

    Article  PubMed  CAS  Google Scholar 

  44. Kohn AD, Takeuchi F, Roth RA. Akt, a pleckstrin homology domain containing kinase, is activated primarily by phosphorylation. J Biol Chem 1996; 271:21, 920–21, 926.

    Google Scholar 

  45. Andjelkovic M, Alessi DR, Meier R, Fernandez A, Lamb NJ, Frech M, Cron P, Cohen P, Lucocq JM, Hemmings BA. Role of translocation in the activation and function of protein kinase B. J Biol Chem 1997; 272:31, 515–31, 524.

    Google Scholar 

  46. Pullen N, Dennis PB, Andjelkovic M, Dufner A, Kozma SC, Hemmings BA, Thomas G. Phosphorylation and activation of p70s6k by PDK1. Science 1998; 279: 707–710.

    Article  PubMed  CAS  Google Scholar 

  47. Marte BM, Downward J. PKB/Akt: connecting phosphoinositide 3-kinase to cell survival and beyond. Trends Biochem Sci 1997; 22: 355–358.

    Article  PubMed  CAS  Google Scholar 

  48. Kulik G, Klippel A, Weber MJ. Antiapoptotic signalling by the insulin-like growth factor I receptor, phosphatidylinositol 3-kinase, and Akt. Mol Cell Biol 1997; 17: 1595–1606.

    PubMed  CAS  Google Scholar 

  49. Ahmed NN, Grimes HL, Bellacosa A, Chan TO, Tsichlis PN. Transduction of interleukin2 antiapoptotic and proliferative signals via Akt protein kinase. Proc Natl Acad Sci USA 1997; 94: 3627–3632.

    Article  PubMed  CAS  Google Scholar 

  50. Kennedy SG, Wagner AJ, Conzen SD, Jordan J, Bellacosa A, Tsichlis PN, Hay N. The PI 3-kinase/Akt signaling pathway delivers an anti-apoptotic signal. Genes Dey 1997; 11: 701–713.

    Article  CAS  Google Scholar 

  51. Kauffmann-Zeh A, Rodriguez-Viciana P, Ulrich E, Gilbert C, Coffer P, Downward J Evan G. Suppression of c-Myc-induced apoptosis by Ras signalling through PI(3)K and PKB. Nature 1997; 385: 544–548.

    Google Scholar 

  52. Khwaja A, Rodriguez-Viciana P, Wennstrom S, Warne PH, Downward J. Matrix adhesion and Ras transformation both activate a phosphoinositide 3-OH kinase and protein kinase B/Akt cellular survival pathway. EMBO J 1997; 16: 2783–2793.

    Article  PubMed  CAS  Google Scholar 

  53. Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y, Greenberg ME. Akt phosphorylation of BAD couples survival signals to the cell-Intrinsic death machinery. Cell 1997; 91: 231–241.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  55. Yaffe MB, Rittinger K, Volinia S, Caron PR, Aitken A, Leffers H, Gamblin SJ, Smerdon SJ, Cantley LC. The structural basis for 14–3–3: Phosphopeptide binding specificity. Cell 1997; 91: 961 – 971.

    Article  PubMed  CAS  Google Scholar 

  56. Alessi DR, Kozlowski MT, Weng QP, Morrice N, Avruch J. 3-Phosphoinositide-dependent protein kinase 1 (PDK1) phosphorylates and activates the p70 S6 kinase in vivo and in vitro. Curr Biol 1998; 8: 69–81.

    Article  PubMed  CAS  Google Scholar 

  57. Chung J, Grammer TC, Lemon KP, Kazlauskas A, Blenis J. PDGF- and insulin-dependent pp70S6k activation mediated by phosphatidylinositol-3-OH kinase. Nature 1994; 370: 71–75.

    Article  PubMed  CAS  Google Scholar 

  58. Salim K, Bottomley MJ, Querfurth E, Zvelebil MJ, Gout I, Scaife R, Margolis RL, Gigg R, Smith CI, Driscoll PC, Waterfield MD, Panayotou G. Distinct specificity in the recognition of phosphoinositides by the pleckstrin homology domains of dynamin and Bruton’s tyrosine kinase. EMBO J 1996; 15: 6241–6250.

    PubMed  CAS  Google Scholar 

  59. Fukuda M, Kojima T, Kabayama H, Mikoshiba K. Mutation of the pleckstrin homology domain of Bruton’s tyrosine kinase in immunodeficiency impaired inositol 1,3,4,5-tetrakisphosphate binding capacity. J Biol Chem 1996; 271:30, 303–30, 306.

    Google Scholar 

  60. Li Z, Wahl MI, Eguinoa A, Stephens LR, Hawkins PT, Witte ON. Phosphatidylinositol 3-kinase-gamma activates Bruton’s tyrosine kinase in concert with Src family kinases. Proc Natl Acad Sci USA 1997; 94:13, 820–13, 825.

    Google Scholar 

  61. Scharenberg AM, El-Hillal O, Fruman DA, Beitz LO, Li Z, Lin S, Gout I, Cantley LC, Rawlings DJ, Kinet J-P. Phosphatidylinositol-3,4,5-trisphosphate (Ptdlns-3,4,5-P3)/ Tec kinase-dependent calcium signaling pathway: A target for SHIP-mediated inhibitory signals. EMBO J 1998; 17: 1961–1972.

    Article  PubMed  CAS  Google Scholar 

  62. August A, Sadra A, Dupont B, Hanafusa H. Src-induced activation of inducible T cell kinase (ITK) requires phosphatidylinositol 3-kinase activity and the Pleckstrin homology domain of inducible T cell kinase. Proc Natl Acad Sci USA 1997; 94:11, 227–11, 232.

    Google Scholar 

  63. Hall A. Rho GTPases and the actin cytoskeleton. Science 1998; 279: 509–514.

    Article  PubMed  CAS  Google Scholar 

  64. Chen RH, Corbalan-Garcia S, Bar-Sagi D. The role of the PH domain in the signal-dependent membrane targeting of Sos. EMBO J 1997; 16: 1351–1359.

    Article  PubMed  CAS  Google Scholar 

  65. Olivier JP, Raabe T, Henkemeyer M, Dickson B, Mbamalu G, Margolis B, Schlessinger J, Hafen E, Pawson T. A Drosophila SH2–SH3 adaptor protein implicated in coupling the sevenless tyrosine kinase to an activator of Ras guanine nucleotide exchange, Sos. Cell 1993; 73: 179–191.

    Article  PubMed  CAS  Google Scholar 

  66. Hu P, Margolis B, Skolnik EY, Lammers R, Ullrich A, Schlessinger AJ. Interaction of phosphatidylinositol 3-kinase-associated p85 with epidermal growth factor and platelet-derived growth factor receptors. Mol Cell Biol 1992; 12: 981–990.

    PubMed  CAS  Google Scholar 

  67. Reif K, Nobes CD, Thomas G, Hall A, Cantrell DA. Phosphatidylinositol 3-kinase signals activate a selective subset of Rac/Rho-dependent effector pathways. Curr Biol 1996; 6: 1445–1455.

    Article  PubMed  CAS  Google Scholar 

  68. Keely PJ, Westwick JK, Whitehead IP, Der CJ, Parise LV. Cdc42 and Racl induce integrinmediated cell motility and invasiveness through PI(3)K. Nature 1997; 390: 632–636.

    Article  PubMed  CAS  Google Scholar 

  69. Nimnual AS, Yatsula BA, Bar-Sagi D. Coupling of Ras and Rac guanosine triphosphatases through the Ras exchanger Sos. Science 1998; 279: 560–563.

    Article  PubMed  CAS  Google Scholar 

  70. Zheng Y, Bagrodia S, Cerione RA. Activation of phosphoinositide 3-kinase activity by Cdc42Hs binding to p85. J Biol Chem 1994; 269:18, 727–18, 730.

    Google Scholar 

  71. Tolias KF, Cantley LC, Carpenter CL. Rho family GTPases bind to phosphoinositide kinases. J Biol Chem 1995; 270:17, 656–17, 659.

    Google Scholar 

  72. Han J, Luby-Phelps K, Das B, Shu X, Xia Y, Mosteller RD, Krishna UM, Falck JR, White MA, Broek D. Role of substrates and products of PI 3-kinase in regulating activation of Rac-related guanosine triphosphatases by Vay. Science 1998; 279: 558–560.

    Article  PubMed  CAS  Google Scholar 

  73. Ridley AJ, Paterson HF, Johnston CL, Diekmann D, Hall A. The small GTP-binding protein rac regulates growth factor-induced membrane ruffling. Cell 1992; 70: 401–410.

    Article  PubMed  CAS  Google Scholar 

  74. Rodriguez-Viciana P, Warne PH, Khwaja A, Marte BM, Pappin D, Das P, Waterfield MD, Ridley A, Downward J. Role of phosphoinositide 3-OH kinase in cell transformation and control of the actin cytoskeleton by Ras. Cell 1997; 89: 457–467.

    Article  PubMed  CAS  Google Scholar 

  75. Chardin P, Paris S, Antonny B, Robineau S, Beraud-Dufour S, Jackson CL, Chabre M. A human exchange factor for ARF contains Sec7- and pleckstrin-homology domains. Nature 1996; 384: 481–484.

    Article  PubMed  CAS  Google Scholar 

  76. Kolanus W, Nagel W, Schiller B, Zeitlmann L, Godar S, Stockinger H, Seed B. Alpha L beta 2 integrin/LFA-1 binding to ICAM-1 induced by cytohesin-1, a cytoplasmic regulatory molecule. Cell 1996; 86: 233–242.

    Article  PubMed  CAS  Google Scholar 

  77. Klarlund JK, Guilherme A, Holik JJ, Virbasius JV, Chawla A, Czech MP. Signaling by phosphoinositide-3,4,5-trisphosphate through proteins containing pleckstrin and Sec7 homology domains. Science 1997; 275: 1927–1930.

    Article  PubMed  CAS  Google Scholar 

  78. Klarlund JK, Rameh LE, Cantley LC, Buxton JM, Holik JJ, Sakelis C, Patki V, Corvera S, Czech MP. Regulation of GRP1-catalyzed ADP ribosylation factor guanine nucleotide exchange by phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 1998; 273: 1859–1862.

    Article  PubMed  CAS  Google Scholar 

  79. Paris S, Beraud-Dufour S, Robineau S, Bigay J, Antonny B, Chabre M, Chardin P. Role of protein-phospholipid interactions in the activation of ARF1 by the guanine nucleotide exchange factor Arno. J Biol Chem 1997; 272:22, 221–22, 226.

    Google Scholar 

  80. Hammonds-Odie LP, Jackson TR, Profit AA, Blader IJ, Turck CW, Prestwich GD, Theibert AB. Identification and cloning of centaurin-alpha. A novel phosphatidylinositol 3,4,5trisphosphate-binding protein from rat brain. J Biol Chem 1996; 271:18, 859–18, 868.

    Google Scholar 

  81. Li G, D’Souza-Schorey C, Barbieri MA, Roberts RL, Klippel A, Williams LT, Stahl PD. Evidence for phosphatidylinositol 3-kinase as a regulator of endocytosis via activation of Rab5. Proc Natl Acad Sci USA 1995; 92:10, 207–10, 211.

    Google Scholar 

  82. Rameh LE, Chen C-S, Cantley LC. Phosphatidylinositol-3,4,5-P3 interacts with SH2 domains and modulates phosphoinositide 3-kinase association with tyrosine-phosphorylated proteins. Cell 1995; 83: 1–20.

    Article  Google Scholar 

  83. Bae YS, Cantley LG, Chen C-S, Kim S-R, Kwon K-S, Rhee SG. Activation of phospholipase C-y by phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 1998; 273: 4465–4469.

    Article  PubMed  CAS  Google Scholar 

  84. Barker SA, Caldwell KK, Hall A, Martinez AM, Pfeiffer JR, Oliver JM, Wilson BS. Wortmannin blocks lipid and protein kinase activities associated with PI 3-kinase and inhibits a subset of responses induced by Fc epsilon R1 cross-linking. Mol Biol Cell 1995; 6: 1145–1158.

    PubMed  CAS  Google Scholar 

  85. Vossebeld PJ, Homburg CH, Schweizer RC, Ibarrola I, Kessler J, Koenderman L, Roos D, Verhoeven AJ. Tyrosine phosphorylation-dependent activation of phosphatidylinositide 3-kinase occurs upstream of Ca’-signalling induced by Fcgamma receptor cross-linking in human neutrophils. Biochem J 1997; 323: 87–94.

    PubMed  CAS  Google Scholar 

  86. Falasca M, Logan SK, Lehto VP, Baccante G, Lemmon MA, Schlessinger J. Activation of phospholipase Cgamma by PI 3-kinase-induced PH domain-mediated membrane targeting. EMBO J 17: 414–422.

    Google Scholar 

  87. Lopez-Ilasaca M, Crespo P, Pellici PG, Gutkind JS, Wetzker R. Linkage of G protein-coupled receptors to the MAPK signaling pathway through PI 3-kinase gamma. Science 1997; 275: 394–397.

    Article  PubMed  CAS  Google Scholar 

  88. Newton AC. Regulation of protein kinase C. Curr Opin Cell Biol 1997; 9: 161–167.

    Article  PubMed  CAS  Google Scholar 

  89. Toker A, Meyer M, Reddy KK, Falck JR, Aneja R, Aneja S, Pana A, Burns DJ, Ballas LM, Cantley LC. Activation of protein kinase C family members by the novel polyphosphoinositides Ptdlns-3,4-P2 and PtdIns-3,4,5-P3. J Biol Chem 1994; 269:32, 358–32, 367.

    Google Scholar 

  90. Moriya S, Kazlauskas A, Akimoto K, Hirai S, Mizuno K, Takenawa T, Fukui Y, Watanabe Y, Ozaki S, Ohno S. Platelet-derived growth factor activates protein kinase C epsilon through redundant and independent signaling pathways involving phospholipase C gamma or phosphatidylinositol 3-kinase. Proc Natl Acad Sci USA 1996; 93: 151–155.

    Article  PubMed  CAS  Google Scholar 

  91. Schiavo G, Gu QM, Prestwich GD, Sollner TH, Rothman JE. Calcium-dependent switching of the specificity of phosphoinositide binding to synaptotagmin. Proc Natl Acad Sci USA 1996; 93:13, 327–13, 332.

    Google Scholar 

  92. MacDougall LK, Domin J, Waterfield MD. A family of phosphoinositide 3-kinases in Drosophila identifies a new mediator of signal transduction. Curr Biol 1995; 5: 1404–1415.

    Article  PubMed  CAS  Google Scholar 

  93. Nakanishi H, Brewer KA, Exton JH. Activation of the zeta isozyme of protein kinase C by phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 1993; 268: 13–16.

    PubMed  CAS  Google Scholar 

  94. Akimoto K, Takahashi R, Moriya S, Nishioka N, Takayanagi J, Kimura K, Fukui Y, Osada S, Mizuno K, Hirai S, Kazlauskas A, Ohno S. EGF or PDGF receptors activate atypical PKClambda through phosphatidylinositol 3-kinase. EMBO J 1996; 15: 788–798.

    PubMed  CAS  Google Scholar 

  95. Palmer RH, Dekker LV, Woscholski R, Le Good JA, Gigg R, Parker P. Activation of PRK1 by phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 1995; 270:22, 412–22, 416.

    Google Scholar 

  96. Schonwasser DC, Marais RM, Marshall CJ, Parker PJ. Activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway by conventional, novel, and atypical protein kinase C isotypes. Mol Cell Biol 1998; 18: 790–798.

    PubMed  CAS  Google Scholar 

  97. Morrison DK, Kaplan DR, Rapp U, Roberts TM. Signal transduction from membrane to cytoplasm: growth factors and membrane-bound oncogene products increase Raf-1 phosphorylation and associated protein kinase activity. Proc Natl Acad Sci USA 1988; 85: 8855–8859.

    Article  PubMed  CAS  Google Scholar 

  98. Cross DA, Alessi DR, Vandenheede JR, McDowell HE, Hundal HS, Cohen P. The inhibition of glycogen synthase kinase-3 by insulin or insulin-like growth factor 1 in the rat skeletal muscle cell line L6 is blocked by wortmannin, but not by rapamycin: Evidence that wortmannin blocks activation of the mitogen-activated protein kinase pathway in L6 cells between Ras and Raf. Biochem J 1994; 303: 21–26.

    PubMed  CAS  Google Scholar 

  99. Duckworth BC, Cantley LC. Conditional inhibition of the mitogen-activated protein kinase cascade by wortmannin. Dependence on signal strength. J Biol Chem 1997; 272:27, 66527, 670.

    Google Scholar 

  100. Rapoport I, Miyazaki M, Boll W, Duckworth B, Cantley LC, Shoelson S, Kirchhausen T. Regulatory interactions in the recognition of endocytic sorting signals by AP-2 complexes. EMBO J 1997; 16: 2240–2250.

    Article  PubMed  CAS  Google Scholar 

  101. Hao W, Tan Z, Prasad K, Reddy KK, Chen J, Prestwich GD, Falck JR, Shears SB, Lafer EM. Regulation of AP-3 function by inositides. Identification of phosphatidylinositol 3,4,5trisphosphate as a potent ligand. J Biol Chem 1997; 272: 6393–6398.

    Article  PubMed  CAS  Google Scholar 

  102. Joly M, Kazlauskas A, Fay FS, Corvera S. Disruption of PDGF receptor trafficking by mutation of its PI-3 kinase binding sites. Science 1994; 263: 684–687.

    Article  PubMed  CAS  Google Scholar 

  103. Yu FX, Sun HQ, Janmey PA, Yin HL. Identification of a polyphosphoinositide-binding sequence in an actin monomer-binding domain of gelsolin. J Biol Chem 1992; 267:14, 61614, 621.

    Google Scholar 

  104. Sohn RH, Chen J, Koblan KS, Bray PF, Goldschmidt-Clermont PJ. Localisation of a binding site for phosphatidylinositol-4,5-bisphosphate on human profilin. J Biol Chem 1995; 270:21, 114–21, 120.

    Google Scholar 

  105. Lu PJ, Shieh WR, Rhee SG, Yin HL, Chen CS. Lipid products of phosphoinositide 3-kinase bind human profilin with high affinity. Biochemistry 1996; 35:14, 027–14, 034.

    Google Scholar 

  106. Hartwig JH, Kung S, Kovacsovics T, Janmey PA, Cantley LC, Stossel TP, Toker A. D3 phosphoinositides and outside-in integrin signaling by glycoprotein IIb-IIIa mediate platelet actin assembly and filopodial extension induced by phorbol 12-myristate 13-acetate. J Biol Chem 1996; 271:32, 986–32, 993.

    Google Scholar 

  107. Hartwig JH, Bokoch G, Carpenter C, Janmey P, Taylor L, Toker A, Stossel TP. Thrombin receptor-ligation and activated Rac uncap actin filament barbed ends through phosphoinositide synthesis in permeabilized human platelets. Cell 1995; 82: 1–20.

    Article  Google Scholar 

  108. Singh SS, Chauhan A, Murakami N, Chauhan VP. Profilin and gelsolin stimulate phosphatidylinositol 3-kinase activity. Biochemistry 1996; 35:16, 544–16, 549.

    Google Scholar 

  109. Leevers SJ, Weinkove D, MacDougall LK, Hafen E, Waterfield MD. The Drosophila phosphoinositide 3-kinase Dp110 promotes cell growth. EMBO J 1996; 15: 6584–6594.

    PubMed  CAS  Google Scholar 

  110. Chang HW, Aoki M, Fruman D, Auger KR, Bellacosa A, Tsichlis PN, Cantley LC, Roberts TM, Vogt PK. Transformation of chicken cells by the gene encoding the catalytic subunit of PI 3-kinase. Science 1997; 276: 1848–1850.

    Article  PubMed  CAS  Google Scholar 

  111. Jimenez C, Jones DR, Rodriguez-Viciana P, Gonzalez-Garcia A, Leonardo E, Wennström S, von Kobbe C, Toran JL, R-Borlado L, Calvo V, Copin SG, Albar JP, Gaspar ML, Diez E, Marcos MAR, Downward J, Martinez AC, Mérida I, Carrera AC. Identification and characterization of a new oncogene derived from the regulatory subunit of phosphoinositide 3-kinase. EMBO J 1998; 17: 743–753.

    Article  PubMed  CAS  Google Scholar 

  112. Bellacosa A, Testa JR, Staal SP, Tsichlis PN. A retroviral oncogene, akt, encoding a serine-threonine kinase containing an SH2-like region. Science 1991; 254: 274–277.

    Article  PubMed  CAS  Google Scholar 

  113. Morris JZ, Tissenbaum HA, Ruvkun G. A phosphatidylinositol-3-OH kinase family member regulating longevity and diapause in Caenorhabditis elegans. Nature 1996; 382: 536–539.

    Article  CAS  Google Scholar 

  114. Zhou K, Takegawa K, Emr SD, Firtel RA. 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 1995; 15: 5645–5656.

    PubMed  CAS  Google Scholar 

  115. Herman PK, Emr SD. Characterization of VPS34, a gene required for vacuolar protein sorting and vacuole segregation in Saccharomyces cerevisiae. Mol Cell Biol 1990; 10: 6742–6754.

    CAS  Google Scholar 

  116. Banfic H, Tang X, Batty IH, Downes CP, Chen C, Rittenhouse SE. A novel integrinactivated pathway forms PKB/Akt-stimulatory phosphatidylinositol 3,4-bisphosphate via phosphatidylinositol 3-phosphate in platelets. J Biol Chem 1998; 273: 13–16.

    Article  PubMed  CAS  Google Scholar 

  117. Sakai N, Sasaki K, Ikegaki N, Shirai Y, Ono Y, Saito N. Direct visualization of the translocation of the gamma-subspecies of protein kinase C in living cells using fusion proteins with green fluorescent protein. J Cell Biol 1997; 139: 1465–1476.

    Article  PubMed  CAS  Google Scholar 

  118. Stauffer TP, Meyer T. Compartmentalized IgE receptor-mediated signal transduction in living cells. J Cell Biol 1997; 139: 1447–1454.

    Article  PubMed  CAS  Google Scholar 

  119. Klippel A, Kavanaugh WM, Pot D, Williams LT. A specific product of phosphatidylinositol 3-kinase directly activates the protein kinase Akt through its pleckstrin homology domain. Mol Cell Biol 1997; 17: 338–344.

    PubMed  CAS  Google Scholar 

  120. Chou MM, Hou W, Johnson J, Graham LK, Lee MH, Chen C-S, Newton AC, Schaffhausen BS, Toker A. Regulation of protein kinase CÇ by PI3-kinase and PDK-1. Curr Biol 1998; 8: 1069–1077.

    Article  PubMed  CAS  Google Scholar 

  121. Bi L, Okake I, Bernard DJ, Wynshaw-Boris A, Nussbaum RL. Proliferative defect and embryonic lethality in mice homozygous for a deletion in the p110a subunit of phosphoinositide 3-kinase. J Biol Chem 1999; 274: 10, 963.

    Google Scholar 

  122. Belham C, Wu S, Avruch J. Intracellular signalling: PDK1-a kinase at the hub of things. Curr Biol 1999; 9: R93–96.

    Article  PubMed  CAS  Google Scholar 

  123. Wurmser AE, Gary JD, Emr SD. Phosphoinositide 3-kinases and their FYVE domain-containing effectors as regulators of vacuolar/lysosomal membrane trafficking pathways. J Biol Chem 1999; 274: 9129–9132.

    Article  PubMed  CAS  Google Scholar 

  124. Fruman DA, Rameh LE, Cantley LC. Phosphoinositide binding domains: embracing 3-phosphate. Cell 1999; 97: 817–820.

    Article  PubMed  CAS  Google Scholar 

  125. Cantley LC, Neel BG. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci USA 1999; 96: 4240–4245.

    Article  PubMed  CAS  Google Scholar 

  126. Terauchi Y, Tsuji Y, Satoh S, Minoura H, Murakami K, Okuno A, Inukai K, Asano T, Kaburagi Y, Ueki K, et al. Increased insulin sensitivity and hypoglycaemia in mice lacking the p85 alpha subunit of phosphoinositide 3-kinase. Nat Genet 1999; 21: 230–235.

    Article  PubMed  CAS  Google Scholar 

  127. Suzuki H, Terauchi Y, Fujiwara M, Aizawa S, Yazaki Y, Kadowaki T, Koyasu S. Xidlike immunodeficiency in mice with disruption of the p85 alpha subunit of phosphoinositide 3-kinase. Science 1999; 283: 390–392.

    Article  PubMed  CAS  Google Scholar 

  128. Fruman DA, Snapper SB, Yballe CM, Davidson L, Yu JY, Alt FW, Cantley LC. Impaired B cell development and proliferation in absence of phosphoinositide 3-kinase p85 alpha. Science 1999; 283: 393–397.

    Article  PubMed  CAS  Google Scholar 

Download references

Authors
  1. David A. Fruman PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lewis C. Cantley PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA

    J. Silvio Gutkind PhD

Rights and permissions

Reprints and permissions

Copyright information

© 2000 Humana Press Inc., Totowa, NJ

About this chapter

Cite this chapter

Fruman, D.A., Cantley, L.C. (2000). PI3-Kinases. In: Gutkind, J.S. (eds) Signaling Networks and Cell Cycle Control. Cancer Drug Discovery and Development. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-218-0_14

Download citation

  • DOI: https://doi.org/10.1007/978-1-59259-218-0_14

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-4684-9695-6

  • Online ISBN: 978-1-59259-218-0

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation