Role of Phosphatidylinositol 3-Kinase in Growth Factor and Oncogene Signaling

  • Lewis Cantley
Conference paper
Part of the NATO ASI Series book series (volume 76)


Phosphatidylinositol 3-kinase (PtdIns 3-Kinase) is an enzyme that phosphorylates the D-3 position of the inositol ring of the membrane lipid, phosphatidylinositol (PtdIns). It was discovered because of its high affinity association with the v-src oncogene product, pp60v-src and with the polyoma middle t/pp60c-src complex in transformed cells (Sugimoto et al., 1984; Whitman et al., 1985; Whitman et al., 1988). Prior to the discovery of this enzyme, the only phosphorylated forms of phosphatidylinositol known to exist in vivo were phosphatidylinositol-4-phosphate (PtdIns-4-P) and phosphatidylinositol-4,5-bisphosphate (PtdIns-4,5-P2). These lipids are intermediates in the canonical PtdIns Turnover Cycle that leads to the well-known second messengers, inositol-1,4,5-trisphosphate and diacylglycerol (Fig. 1). In vitro, PtdIns 3-Kinase can phosphorylate the D-3 position of PtdIns, PtdIns-4-P or PtdIns-4,5-P2 to produce PtdIns-3-P, PtdIns-3,4-P2 and PtdIns-3,4,5-P3 respectively (Auger et al., 1989; Carpenter and Cantley, 1990)). All three of these lipids have now been detected in mammalian cells (Auger et al., 1989; Stephens et al., 1989). The lipid products of PtdIns 3-Kinase are not substrates for the phospholipases type C and are not intermediates in the canonical PtdIns Turnover Cycle (Lips et al., 1989; Serunian et al., 1989). Rather, they appear to be involved in a distinct regulatory process in the cell.


Lipid Product Phospho Tyrosine PDGF Receptor Phosphatidylinositol Kinase Activity Stem Cell Growth Factor 
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  1. Auger, K., Carpenter, C., Piwnica-Worms, H. and Cantley, L. (1991). Polyoma virus middle T antigen/pp60c-src complex associates with purified phosphatidylinositol 3-kinase in vitro. J. Biol. Chem. 267, 5408–5415.Google Scholar
  2. Auger, K. R., Serunian, L. A., Soltoff, S. P., Libby, P. and Cantley, L. C. (1989). PDGF-dependent tyrosine phosphorylation stimulates production of novel polyphosphoinositides in intact cells. Cell 57, 167–75.PubMedCrossRefGoogle Scholar
  3. Booker, G. W., Breeze, A. L., Downing, A. K., Panayotou, G., Gout, I., Waterfield, M. D. and Campbell, I. D. (1992). Structure of an SH2 domain of the p85 alpha subunit of phosphatidylinositol-3-OH kinase. Nature 358, 684–7.PubMedCrossRefGoogle Scholar
  4. Cantley, L. C., Auger, K. R., Carpenter, C. L., Duckworth, B., Graziani, A., Kapeller, R. and Soltoff, S. (1991). Oncogenes and Signal Transduction. Cell 64, 281–302.PubMedCrossRefGoogle Scholar
  5. Carpenter, C. L., Auger, K. A., Shoelson, S. and Cantley, L. C. (1993). Activation of Phosphatidylinositol 3-kinase by phosphotyrosine-containing peptides. (submitted)Google Scholar
  6. Carpenter, C. L. and Cantley, L. C. (1990). Phosphoinositide Kinases. Biochemistry 29 11147–11156.PubMedCrossRefGoogle Scholar
  7. Carpenter, C. L., Duckworth, B., Auger, K. A., Schaffhausen, B. and Cantley, L. C. (1993). A tightly associated serine/threonine protein kinase regulates phosphoinositide 3-kinase activity. Mol. Cell. Biochem. (in press)Google Scholar
  8. Carpenter, C. L., Duckworth, B. C., Auger, K. R., Cohen, B., Schaffhausen, B. S. and Cantley, L. C. (1990). Purification and characterization of phosphoinositide 3-kinase from rat liver. J. Biol. Chem. 265, 19704–19711.PubMedGoogle Scholar
  9. Cicchetti, P., Mayer, B. J., Thiel, G. and Baltimore, D. (1992). Identification of a protein that binds to the SH3 region of Abl and is similar to Bcr and GAP-rho. Science 257, 803–806.PubMedCrossRefGoogle Scholar
  10. Coughlin, S. R., Escobedo, J. A. and Williams, L. T. (1989). Role of phosphatidylinositol kinase in PDGF receptor signal transduction. Science 243, 1191–1194.PubMedCrossRefGoogle Scholar
  11. Diekmann, D., Brill, S., Garrett, M. D., Totty, N., Hsuan, J., Monfries, C., Hall, C., Lim, L. and Hall, A. (1991). Bcr encodes a GTPase-activating protein for p21rac. Nature 351, 400–4002.Google Scholar
  12. Duden, R., Ho, W. C., Allan, V. J. and Kreis, T. E. (1990). What’s new in cytoskeleton-organelle interactions? Relationship between microtubules and the Golgi-apparatus. Pathol Res Pract 186, 535–41.PubMedCrossRefGoogle Scholar
  13. Escobedo, J. A., Navankasattusas, S., Kavanaugh, W. M., Milfay, D., Fried, V. A. and Williams, L. T. (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, 75–82.PubMedCrossRefGoogle Scholar
  14. Fantl, W. J., Escobedo, J. A., Martin, G. A., Turck, C. W., del, R. M., McCormick, F. and Williams, L. T. (1992). Distinct phosphotyrosines on a growth factor receptor bind to specific molecules that mediate different signaling pathways. Cell 69, 413–23.PubMedCrossRefGoogle Scholar
  15. Herman, P. K. and Emr, S. D. (1990). Characterization of VPS34, a gene required for vacuolar protein sorting and vacuole segregation in Saccharomyces cerevisiae. Mol Cell Biol 10, 6742–54.PubMedGoogle Scholar
  16. Hiles, I. D., Otsu, M., Volinia, S., Fry, M. J., Gout, I., Dhand, R., Panayotou, G., Ruiz, L. F., Thompson, A., Totty, N. F., Hsuan, J. J., Courtneidge, S. A., Parker, P. J. and Waterfield, M. D. (1992). Phosphatidylinositol 3-kinase: structure and expression of the 110 kd catalytic subunit. Cell 70, 419–29.PubMedCrossRefGoogle Scholar
  17. Kaplan, D. R., Whitman, M., Schaffhausen, B., Pallas, D. C., White, M., Cantley, L. and Roberts, T. M. (1987). Common elements in growth factor stimulation and oncogenic transformation: 85 kd phosphoprotein and phosphatidylinositol kinase activity. Cell 50, 1021–9.PubMedCrossRefGoogle Scholar
  18. Kelly, K. L., Ruderman, N. B. and Chen, K. S. (1992). Phosphatidylinositol-3-kinase in isolated rat adipocytes. Activation by insulin and subcellular distribution. J Biol Chem 267, 3423–8.PubMedGoogle Scholar
  19. Kucera, G. L. and Rittenhouse, S. E. (1990). Human platelets form 3-phosphorylated phosphoinositides in response to alpha-thrombin, U46619, or GTP gamma S. J Biol Chem 265, 5345–8.PubMedGoogle Scholar
  20. Lips, D. L., Majerus, P. W., Gorga, F. R., Young, A. T. and Benjamin, T. L. (1989). Phosphatidylinositol 3-phosphate is present in normal and transformed fibroblasts and is resistant to hydrolysis by bovine brain phospholipase C II. J. Biol. Chem. 264, 8759–8763.PubMedGoogle Scholar
  21. Mayer, B. J., Jackson, P. K. and Baltimore, D. (1991). The noncatalytic src homology region 2 segment of abl tyrosine kinase binds to tyrosine-phosphorylated cellular proteins with high affinity. Proc. Natl. Acad. Sci. 88, 627–631.PubMedCrossRefGoogle Scholar
  22. Musacchio, A., Noble, M., Pauptit, R., Wierenga, R. and Saraste, M. (1992). Crystal Structure of a Src-homology 3 (SH3) domain. Nature 359, 851–855.PubMedCrossRefGoogle Scholar
  23. Otsu, M., Hiles, I., Gout, I., Fry, M. J., Ruiz, L. F., Panayotou, G., Thompson, A., Dhand, R., Hsuan, J., Totty, N. and et. al. (1991). Characterization of two 85 kd proteins that associate with receptor tyrosine kinases, middle-T/pp60c-src complexes, and PI3-kinase. Cell 65, 91–104.PubMedCrossRefGoogle Scholar
  24. Remillard, B., Petrillo, R., Maslinski, W., Tsudo, M., Strom, T. B., Cantley, L. and Varticovski, L. (1991). Interleukin-2 receptor regulates activation of phosphatidylinositol 3-kinase. J Biol Chem 266, 14167–70.PubMedGoogle Scholar
  25. Ridley, A. J. and Hall, A. (1992). The Small GTP-Binding Protein rho Regulates the Assembly of Focal Adhesions and Actin Stress Fibers in Response to Growth Factors. Cell 70, 389–399.PubMedCrossRefGoogle Scholar
  26. Ridley, A. J., Paterson, H. F., Johnston, C. L., Diekmann, D. and Hall, A. (1992). The Small GTP-Binding Protein rac Regulates Growth Factor-Induced Membrane Ruffling. Cell 70, 401–410.PubMedCrossRefGoogle Scholar
  27. Serunian, L. A., Haber, M. T., Fukui, T., Kim, J. W., Rhee, S. G., Lowenstein, J. M. and Cantley, L. C. (1989). Polyphosphoinositides produced by phosphatidylinositol 3-kinase are poor substrates for phospholipases C from rat liver and bovine brain. J Biol Chem 264, 17809–15.PubMedGoogle Scholar
  28. Shibasaki, F., Homma, Y. and Takenawa, T. (1991). Two types of phosphatidylinositol 3-kinase from bovine thymus. Monomer and heterodimer form. J Biol Chem 266, 8108–14.PubMedGoogle Scholar
  29. Skolnik, E. Y., Margolis, B., Mohammadi, M., Lowenstein, E., Fischer, R., Drepps, A., Ullrich, A. and 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, 83–90.PubMedCrossRefGoogle Scholar
  30. Stephens, L., Hawkins, P. T. and Downes, C. P. (1989). Metabolic and structural evidence for the existence of a third species of polyphosphoinositide in cells: D-phosphatidyl-myo-inositol 3-phosphate. Biochem.J. 259, 267–276.PubMedGoogle Scholar
  31. Sugimoto, Y., Whitman, M., Cantley, L. C. and Erikson, R. L. (1984). Evidence that the Rous sarcoma virus transforming gene product phosphorylates phosphatidylinositol and diacylglycerol. Proc Natl Acad Sci U S A 81, 2117–21.PubMedCrossRefGoogle Scholar
  32. Traynor-Kaplan, A. E., Harris, A. L., Thompson, B. L., Taylor, P. and Sklar, L. A. (1988). An inositol tetrakisphosphate-containing phospholipid in activated neutrophils. Nature 334, 353–356.PubMedCrossRefGoogle Scholar
  33. Waksman, G., Kominos, D., Robertson, S. C., Pant, N., Baltimore, D., Birge, R. B., Cowburn, D., Hanafusa, H., Mayer, B. J., Overduin, M. and et, al. (1992). Crystal structure of the phosphotyrosine recognition domain SH2 of v-src complexed with tyrosine-phosphorylated peptides. Nature 358, 646–53.PubMedCrossRefGoogle Scholar
  34. Whitman, M., Downes, C.P., Keeler, M., Keller, T. and Cantley, L. (1988) Type I Phosphatidylinositol Kinase Makes a Novel Inositol Phospholipid, Phosphatidylinositol-3-phosphate Nature 332, 644–646.PubMedCrossRefGoogle Scholar
  35. Whitman, M., Kaplan, D., Roberts, T. and Cantley, L. (1987). Evidence for two distinct phosphatidylinositol kinases in fibroblasts: Implications for cellular regulation. Biochem J 247, 165–74.PubMedGoogle Scholar
  36. Whitman, M., Kaplan, D. R., Schaffhausen, B., Cantley, L. and Roberts, T. M. ( 1985). Association of phosphatidylinositol kinase activity with polyoma middle-T competent for transformation. Nature 315, 239–42.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1993

Authors and Affiliations

  • Lewis Cantley
    • 1
  1. 1.Dept. of Cellular and Molecular PhysiologyHarvard Medical School and Division of Signal Transduction, Beth Israel HospitalBostonUSA

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