PI 3-Kinase and Receptor-Linked Signal Transduction

  • Brian C. Duckworth
  • Lewis C. Cantley
Part of the Handbook of Lipid Research book series (HLRE, volume 8)


Classical phosphoinositide (PI) metabolism leading to the well-known second messengers diacylglycerol (DAG) and inositol-1,4,5-trisphosphate (InsP3), was elucidated more than 10 years ago (Fig. 4-1A). Many mitogenic signals stimulate PI turnover and transformed cells have constitutively activated PI turnover. It was work on this classical pathway that eventually led to the discovery of the novel PI pathway. Let us first look briefly at the classical pathway, in which phosphatidylinositol (Ptdlns) is phosphorylated by PtdIns 4-kinase to PtdIns-4-P, which is subsequently phosphorylated by PtdIns-4-P 5-kinase to form PtdIns-4,5-P2. Much of the PtdIns-4,5-P2 in the cell is found on the inner leaflet of the plasma membrane. This lipid can serve as a substrate for PI-specific phospholipase C (PLC), liberating DAG and IP3. IP3 is a water-soluble molecule which, when released into the cytosol, acts to liberate intracellular stores of Ca2+, increasing the intracellular concentration of Ca2+ from the resting level of ~110 nM to 400–1000 nM, which in turn can activate a number of Ca2+-sensitive enzymes and channels. The DAG released from Ptdlns-4,5-P2 remains in the membrane and serves as a cofactor in activating many of the protein kinase C (PKC) isotypes.


PDGF Receptor Lipid Kinase Phosphatidylinositol Kinase Activity PDGF Stimulation Lipid Kinase Activity 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Arcaro, A., and Wymann, M. P., 1993, Wortmannin is a potent phosphatidylinositol 3-kinase inhibitor: The role of phosphatidylinositol 3,4,5-trisphosphate in neutrophil responses, Binchem. J. 296: 297–301.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: 167–175.PubMedCrossRefGoogle Scholar
  3. Auger, K. R., Carpenter, C. L., Shoelson, S. E., Piwnica, W. H., and Cantley, L. C., 1992, Polyoma virus middle T antigen—pp60c-src complex associates with purified phosphatidylinositol 3-kinase in vitro, J BioL Chem. 267: 5408–5415.PubMedGoogle Scholar
  4. Backer, J. M., Myers, M. J., Shoelson, S. E., Chin, D. J., Sun, X. J., Miralpeix, M., Hu, P., Margolis, B., Skolnik, E. Y., Schlessinger, J., and White, M. E, 1992a, Phosphatidylinositol 3’-kinase is activated by association with IRS•1 during insulin stimulation, EMBO J 11: 3469–3479.PubMedGoogle Scholar
  5. Backer, J. M., Schroeder, G. G., Kahn, C. R., Myers, M.J., Wilden, P. A., Cahill, D. A., and White, M. F., 1992b, Insulin stimulation of phosphatidylinositol 3-kinase activity maps to insulin receptor regions required for endogenous substrate phosphorylation, J. Biol. Chem. 267: 1367–1374.PubMedGoogle Scholar
  6. Berger, J., Hayes, N., Szalkowski, D. M., and Zhang, B., 1994, PI 3-kinase activation is required for insulin stimulation of glucose transport into L6 myotubes, Biochem. Biophys. Res. Commun. 205: 570–576.PubMedCrossRefGoogle Scholar
  7. Berra, E., Diaz, M. M., Dominguez, I., Municio, M. M., Sanz, L., Lozano, J., Chapkin, R. S., and Moscat, J., 1993, Protein kinase C zeta isoform is critical for mitogenic signal transduction, Cell 74: 555–563.PubMedCrossRefGoogle Scholar
  8. Blaikie, P., Immanuel, D., Wu, J., Li, N., Yajnik, V., and Margolis, B., 1994, A region in Shc distinct from the SH2 domain can bind tyrosine-phosphorylated growth factor receptors, J. Biol. Chem. 269: 32031–32034.PubMedGoogle Scholar
  9. Blumer, K. J., and Johnson, G. L., 1994, Diversity in function and regulation of MAP kinase pathways, Trends Biochem. Sci. 19: 236–240.PubMedCrossRefGoogle Scholar
  10. Boguski, M. S., and McCormick, E, 1993, Proteins regulating Ras and its relatives, Nature 366: 643–654.PubMedCrossRefGoogle Scholar
  11. 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: 684–687.PubMedCrossRefGoogle Scholar
  12. Booker, G. W., Gout, I., Downing, A. K., Driscoll, P. C., Boyd, J., Waterfield, M. D., and Campbell, I. D., 1993, Solution structure and ligand-binding site of the SH3 domain of the p85 alpha subunit of phosphatidylinositol 3-kinase, Cell 73: 813–822.PubMedCrossRefGoogle Scholar
  13. Burgering, B. M. T., and Bos, J. L., 1995, Regulation of Ras-mediated signalling; more than one way to skin a cat, Trends Biochem. Sci. 20: 18–22.PubMedCrossRefGoogle Scholar
  14. Cacace, A. M., Guadagno, S. N., Krauss, R. S., Fabbro, D., and Weinstein, I. B., 1993, The epsilon isoform of protein kinase C is an oncogene when overexpressed in rat fibroblasts, Oncogene 8: 2095–2104.PubMedGoogle Scholar
  15. Campbell, K. S., Ogris, E., Burke, B., Su, W., Auger, K. R., Druker, B.J., Schaffhausen, B. S., Roberts, T. M., and Pallas, D. C., 1994, Polyoma middle tumor antigen interacts with SHC protein via the NPTY (Asn-Pro-Thr-Tyr) motif in middle tumor antigen, Proc. Natl. Acad. Sci. USA 91: 6344–6348.PubMedCrossRefGoogle Scholar
  16. Cantley, L. C., Auger, K. R., Carpenter, C., Duckworth, B., Graziani, A., Kapeller, R., and Soltoff, S., 1991, Oncogenes and signal transduction, Cell 64: 281–302.PubMedCrossRefGoogle Scholar
  17. 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
  18. Carpenter, C. L., Auger, K. R., Chanudhuri, M., Yoakim, M., Schaffhausen, B., Shoelson, S., and Cantley, L. C., 1993a, Phosphoinositide 3-kinase is activated by phosphopeptides that bind to the SH2 domains of the 85-kDa subunit, J. Biol. Chem. 268: 9478–9483.PubMedGoogle Scholar
  19. Carpenter, C. L., Auger, K. R., Duckworth, B. C., Hou, W. M., Schaffhausen, B., and Cantley, L. C., 1993b, A tightly associated serine/threonine protein kinase regulates phosphoinositide 3-kinase activity, Mol. Cell. Biol. 13: 1657–1665.PubMedGoogle Scholar
  20. Carraway, K. L., III, and Cantley, L. C., 1994, A neu acquaintance for erbB3 and erbB4: A role for receptor heterodimerization in growth signaling, Cell 78: 5–8.PubMedCrossRefGoogle Scholar
  21. Carraway, K. L., III, Soltoff, S. P., Diamonti, A. J., and Cantley, L. C., 1995, Heregulin stimulates mitogenesis and phosphatidylinositol 3-kinase in mouse fibroblasts transfected with erbB2/neu and erb3, J. Biol. Chem. 270: 7111–7116.PubMedCrossRefGoogle Scholar
  22. Carter, A. N., and Downes, C. P., 1992, Phosphatidylinositol 3-kinase is activated by nerve growth factor and epidermal growth factor in PC12 cells [published erratum appears in J. Biol. Chem. 1992, 267:23434], J. Biol. Chem. 267: 14563–14567.PubMedGoogle Scholar
  23. Chant, J., and Stowers, L., 1995, GTPase cascades choreographing cellular behavior: Movement, morphogenesis, and more, Cell 81: 1–4.PubMedCrossRefGoogle Scholar
  24. Cheatham, B., Vlahos, C. J., Cheatham, L., Wang, L., Blenis, J., and Kahn, C. R., 1994, Phosphatidylinositol 3-kinase activation is required for insulin stimulation of pp70 S6 kinase, DNA synthesis, and glucose transporter translocation, Mol. Cell. Biol. 14: 4902–4911.PubMedGoogle Scholar
  25. Chen, H. C., and Guan, J. L., 1994a, Association of focal adhesion kinase with its potential substrate phosphatidylinositol 3-kinase, Proc. Natl. Acad. Sci. USA 91: 10148–10152.PubMedCrossRefGoogle Scholar
  26. Chen, H. C., and Guan, J. L., 1994b, Stimulation of phosphatidylinositol 3’-kinase association with focal adhesion kinase by platelet-derived growth factor, J Biol. Chem. 269: 31229–31233.PubMedGoogle Scholar
  27. Chen, W.J., Goldstein, J. L., and Brown, M. S., 1990, NPXY, a sequence often found in cytoplasmic tails, is required for coated pit-mediated internalization of the low density lipoprotein receptor, J. Biol. Chem. 265: 3116–3128.PubMedGoogle Scholar
  28. Cherniack, A. D., Klarlund, J. K., and Czech, M. P., 1994, Phosphorylation of the Ras nucleotide exchange factor son of sevenless by mitogen-activated protein kinase, J. Biol. Chem. 269: 47174720.Google Scholar
  29. Choudhury, G. G., Wang, L. M., Pierce, J., Harvey, S. A., and Sakaguchi, A. Y., 1991, A mutational analysis of phosphatidylinositol-3-kinase activation by human colony-stimulating factor-1 receptor, J. Biol. Chem. 266: 8068–8072.PubMedGoogle Scholar
  30. Chung, J., Grammer, T. C., Lemon, K. P., Kazlauskas, A., and Blenis, J., 1994, PDGF- and insulin-dependent pp70S6k activation mediated by phosphatidylinositol-3-OH kinase, Nature 370: 71–75.Google Scholar
  31. Clarke, F. J., Young, P. W., Yonezawa, K., Kasuga, M., and Holman, G. D., 1994, Inhibition of the translocation of GLUT1 and GLUT4 in 3T3–L1 cells by the phosphatidylinositol 3-kinase inhibitor, wortmannin, Biochem. j 306: 631–635.Google Scholar
  32. Cohen, B., Yoakim, M., Piwnica, W. H., Roberts, T. M., and Schaffhausen, B. S., 1990, Tyrosine phosphorylation is a signal for the trafficking of pp85, an 85-kDa phosphorylated polypeptide associated with phosphatidylinositol kinase activity, Proc. Natl. Acad. Sci. USA 87: 4458–4462.PubMedCrossRefGoogle Scholar
  33. Cooper, J. A., and Kashishian, A., 1993, In vivo binding properties of SH2 domains from GTPaseactivating protein and phosphatidylinositol 3-kinase, Mol. Cell. Biol. 13: 1737–1745.PubMedGoogle Scholar
  34. 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
  35. Courtneidge, S. A., and Heber, A., 1987, An 81 kd protein complexed with middle T antigen and pp60c-5«: A possible phosphatidylinositol kinase, Cell 50: 1031–1037.PubMedCrossRefGoogle Scholar
  36. Cross, D. A., Alessi, D. R., Vandenheede, J. R., McDowell, H. E., Hundal, H. S., and Cohen, P., 1994, 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 303: 21–26.PubMedGoogle Scholar
  37. Dhand, R., Hara, K., Hiles, I., Box, B., Gout, I., Panayotou, G., Fry, M.J., Yonezawa, K., Kasuga, M., and Waterfield, M. D., 1994a, PI 3-kinase: Structural and functional analysis of intersubunit interactions, EMBO J. 13: 511–521.Google Scholar
  38. Dhand, R., Hiles, I., Panayotou, G., Roche, S., Fry, M. J., Gout, I., Totty, N. F., Truong, O., Vicendo, P., Yonezawa, K., Kasuga, M., Courtneidge, S. A., and Waterfield, M. D., 1994b, PI 3-kinase is a dual specificity enzyme: Autoregulation by an intrinsic protein-serine kinase activity, EMBO j 13: 522–533.Google Scholar
  39. Dilworth, S. M., Brewster, C. E., Jones, M. D., Lanfrancone. L., Pelicci, G., and Pelicci, P. G., 1994, Transformation by polyoma virus middle T-antigen involves the binding and tyrosine phosphorylation of Shc, Nature 367: 87–90.PubMedCrossRefGoogle Scholar
  40. Druker, B. J., Ling, L. E., Cohen, B., Roberts, T. M., and Schaffhausen, B. S., 1990, A completely transformation-defective point mutant of polyomavirus middle T antigen which retains full associated phosphatidylinositol kinase activity, J. Virol. 64: 4454–4461.PubMedGoogle Scholar
  41. Eck, M. J., Shoelson, S. E., and Harrison, S. C., 1993, Recognition of a high-affinity phosphotyrosyl peptide by the Src homology-2 domain of p561Vk, Nature 362: 87–91.PubMedCrossRefGoogle Scholar
  42. Eck, M.J., Atwell, S. K., Shoelson, S. E., and Harrison, S. C., 1994, Structure of the regulatory domains of the Src-family tyrosine kinase Lck, Nature 368: 764–769.PubMedCrossRefGoogle Scholar
  43. End, P., Gout, I., Fry, M. J., Panayotou, G., Dhand, R., Yonezawa, K., Kasuga, M., and Waterfield, M. D., 1993, A biosensor approach to probe the structure and function of the p85 alpha subunit of the phosphatidylinositol 3-kinase complex, J. Biol. Chem. 268: 10066–10075.Google Scholar
  44. Endemann, G., Yonezawa, K, and Roth, R. A., 1990, Phosphatidylinositol kinase or an associated protein is a substrate for the insulin receptor tyrosine kinase, J Biol. Chem. 265: 396–400.PubMedGoogle Scholar
  45. 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.Google Scholar
  46. Fanti, W. J., Escobedo, J. A., Martin, G. A., Turck, C. W., del Rosario, M., McCormick, E, and Williams, L. T., 1992, Distinct phosphotyrosines on a growth factor receptor bind to specific molecules that mediate different cellular signaling pathways, Cell 69: 413–423.CrossRefGoogle Scholar
  47. Fedi, P., Pierce, J. H., di Fiore, P., and Kraus, M. H., 1994, Efficient coupling with phosphatidylinositol 3-kinase, but not phospholipase C gamma or GTPase-activating protein, distinguishes ErbB-3 signaling from that of other ErbB/EGFR family members, Mol. Cell. Biol. 14: 492–500.PubMedGoogle Scholar
  48. Feng, S., Chen, J. K., Yu, H., Simon, J. A., and Schreiber, S. L., 1994, Two binding orientations for peptides to the Src SH3 domain: Development of a general model for SH3—ligand interactions, Science 266: 1241–1247.Google Scholar
  49. Flanagan, C. A., Schnieders, E. A., Emerick, A. W., Kunisawa, R., Admon, A., and Thorner, J., 1993, Phosphatidylinositol 4-kinase: Gene structure and requirement for yeast cell viability, Science 262: 1444–1448.PubMedCrossRefGoogle Scholar
  50. Folli, F., Saad, M. J., Backer, J. M., and Kahn, C. R., 1992, Insulin stimulation of phosphatidylinositol 3-kinase activity and association with insulin receptor substrate 1 in liver and muscle of the intact rat, J. Biol. Chem. 267: 22171–22177.Google Scholar
  51. Fry, M. J., Panayotou, G., Dhand, R., Ruiz, L. F., Gout, I., Nguyen, O., Courtneidge, S. A., and Waterfield, M. D., 1992, Purification and characterization of a phosphatidylinositol 3-kinase complex from bovine brain by using phosphopeptide affinity columns, Biochem. J 288: 383–393.Google Scholar
  52. Fukui, Y, Saltiel, A. R., and Hanafusa, H., 1991, Phosphatidylinositol-3 kinase is activated in v-src, v-yes, and v-fps transformed chicken embryo fibroblasts, Oncogene 6: 407–411.PubMedGoogle Scholar
  53. Giorgetti, S., Ballotti, R., Kowalski, C. A., Cormont, M., and Van Obberghen, E., 1992, Insulin stimulates phosphatidylinositol-3-kinase activity in rat adipocytes, Eur. J Biochem. 207: 599–606.PubMedCrossRefGoogle Scholar
  54. Giorgetti, S., Ballotti, R., Kowalski, C. A., Tartare, S., and Van Obberghen, E., 1993, The insulin and insulin-like growth factor-I receptor substrate IRS-1 associates with and activates phosphatidylinositol 3-kinase in vitro, J Biol. Chem. 268: 7358–7364.PubMedGoogle Scholar
  55. Goldschmidt-Clermont, P. J., Machesky, L. M., Baldassare, J. J., and Pollard, T. D., 1990, The actin-binding protein profilin binds to PIP2 and inhibits its hydrolysis by phospholipase C, Science 247: 1575–1578.PubMedCrossRefGoogle Scholar
  56. Goldschmidt-Clermont, P. J., Kim, J. W., Machesky, L. M., Rhee, S. G., and Pollard, T. D., 1991, Regulation of phospholipase C-gamma 1 by profilin and tyrosine phosphorylation, Science 251: 1231–1233.Google Scholar
  57. Graziani, A., Ling, L. E., Endemann, G., Carpenter, C. L., and Cantley, L. C., 1992, Purification and characterization of human erythrocyte phosphatidylinositol 4-kinase. Phosphatidylinositol 4-kinase and phosphatidylinositol 3-monophosphate 4-kinase are distinct enzymes, Biochem. J 284: 39–45.PubMedGoogle Scholar
  58. Guy, P. M., Platko, J. V., Cantley, L. C., Cerione, R. A., and Carraway, K. L., ííI,1994, Insect cell-expressed p180erbB3 possesses an impaired tyrosine kinase activity, Proc. Natl. Acad. Sci. USA 91: 8132–8136.Google Scholar
  59. Hadari, Y. R., Tzahar, E., Nadiv, O., Rotenberg, P., Roberts, C. J., LeRoith, D., Yarden, Y., and Zick, Y., 1992, Insulin and insulinomimetic agents induce activation of phosphatidylinositol 3’-kinase upon its association with pp185 (IRS-1) in intact rat livers [published erratum appears in./ Biol. Chem. 1993, 268:9156], J. Biol. Chem. 267: 17483–17486.PubMedGoogle Scholar
  60. Hara, K., Yonezawa, K., Sakaue, H., Ando, A., Kotani, K., Kitamura, T., Kitamura, Y, Ueda, H., Stephens, L., Jackson, T. R., Hawkins, P. T., Dhand, R., Clark, A. E., Holman, G. D., Waterfield, M. D., and Kasuga, M., 1994, 1-Phosphatidylinositol 3-kinase activity is required for insulin-stimulated glucose transport but not for RAS activation in CHO cells, Proc. Natl. Acad. Sci. USA 91:7415–7419.Google Scholar
  61. Hawkins, P. T., Jackson, T. R., and Stephens, L. R., 1992, Platelet-derived growth factor stimulates synthesis of Ptdlns(3,4,5)P3 by activating a Ptdlns(4,5)P2 3-OH kinase, Nature 358: 157–159.PubMedCrossRefGoogle Scholar
  62. Hayashi, H., Miyake, N., Kanai, F., Shibasaki, F., Takenawa, T., and Ebina, Y, 1991, Phosphorylation in vitro of the 85 kDa subunit of phosphatidylinositol 3-kinase and its possible activation by insulin receptor tyrosine kinase, Biochem. 280: 769–775.Google Scholar
  63. Hayashi, H., Kamohara, S., Nishioka, Y, Kanai, E, Miyake, N., Fukui, Y, Shibasaki, E, Takenawa, T., and Ebina, Y, 1992, Insulin treatment stimulates the tyrosine phosphorylation of the alpha-type 85kDa subunit of phosphatidylinositol 3-kinase in vivo, j Biol. Chem. 267: 22575–22580.PubMedGoogle Scholar
  64. Hayashi, H., Nishioka, Y, Kamohara, S., Kanai, E, Ishii, K, Fukui, Y., Shibasaki, E, Takenawa, T., Kido, H., Katsunuma, N., and Ebina, Y., 1993, The alpha-type 85-kDa subunit of phosphatidylinositol 3-kinase is phosphorylated at tyrosines 368, 580, and 607 by the insulin receptor, J. Biol. Chem. 268: 7107–7117.PubMedGoogle Scholar
  65. Heitman, J., Movva, N. R., and Hall, M. N., 1991, Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast, Science 253: 905–909.PubMedCrossRefGoogle Scholar
  66. Herbst, J. J., Andrews, G., Contillo, L., Lamphere, L., Gardner, J., Lienhard, G. E., and Gibbs, E. M., 1994, Potent activation of phosphatidylinositol 3’-kinase by simple phosphatyrosine peptides derived from insulin receptor substrate 1 containing two YMXM motifs for binding SH2 domains, Biochemistry 33: 9376–9381.PubMedCrossRefGoogle Scholar
  67. 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: 6742–6754.PubMedGoogle Scholar
  68. Hiles, I. D., Otsu, M., Volinia, S., Fry, M. J., Gout, I., Dhand, R., Panayotou, G., Ruiz, L. E, 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: 419–429.PubMedCrossRefGoogle Scholar
  69. Holt, K. H., Olson, L., Moye, R. W., and Pessin, J. E., 1994, Phosphatidylinositol 3-kinase activation is mediated by high-affinity interactions between distinct domains within the p110 and p85 subunits, Mol. Cell. Biol. 14: 42–49.PubMedGoogle Scholar
  70. Hu, P., and Schlessinger, J., 1994, Direct association of p110 beta phosphatidylinositol 3-kinase with p85 is mediated by an N-terminal fragment of p110 beta, Mol. Cell. Biol. 14: 2577–2583.PubMedCrossRefGoogle Scholar
  71. Hu, P., Margolis, B., Skolnik, E. Y., Lammers, R., Ullrich, A., and Schlessinger, J., 1992, Interaction of phosphatidylinositol 3- kinase-associated p85 with epidermal growth factor and platelet-derived growth factor receptors, Mol. Cell. Biol. 12: 981–990.PubMedGoogle Scholar
  72. Hu, P., Mondino, A., Skolnik, E. Y., and 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: 7677–7688.PubMedGoogle Scholar
  73. Jackson, T. R., Stephens, L. R., and Hawkins, P. T., 1992, Receptor specificity of growth factor-stimulated synthesis of 3-phosphorylated inositol lipids in Swiss 3T3 cells,/ Biol. Chem. 267: 1662716636.Google Scholar
  74. Janmey, P. A., 1994, Phosphoinositides and calcium as regulators of cellular actin assembly and disassembly, Annu. Rev. Physiol. 56: 169–191.CrossRefGoogle Scholar
  75. Jefferies, H. B., Reinhard, C., Kozma, S. C., and Thomas, G., 1994, Rapamycin selectively represses translocation of the “polypyrimidine tract” mRNA family, Proc. Natl. Acad. Sci. USA 91: 4441–4445.PubMedCrossRefGoogle Scholar
  76. Jhun, B. H., Rose, D. W., Seely, B. L., Rameh, L., Cantley, L., Saltiel, A. R., and Olefsky, J. M., 1994, Microinjection of the SH2 domain of the 85-kilodalton subunit of phosphatidylinositol 3-kinase inhibits insulin-induced DNA synthesis and c-fos expression, Mol. Cell. Biol. 14: 7466–7475.PubMedGoogle Scholar
  77. Johnson, D. I., and Pringle, J. R., 1990, Molecular characterization of CDC42, a Saccharomyces cerevisiae gene involved in the development of cell polarity, J Cell Biol. 111: 143–152.PubMedCrossRefGoogle Scholar
  78. Kapeller, R., Chen, K. S., Yoakim, M., Schaffhausen, B. S., Backer, J., White, M. E, Cantley, L. C., and Ruderman, N. B., 1991, Mutations in the juxtamembrane region of the insulin receptor impair activation of phosphatidylinositol 3-kinase by insulin, Mol. Endocrinol. 5: 769–777.PubMedCrossRefGoogle Scholar
  79. Kapeller, R., Prasad, K. V., Janssen, O., Hou, W., Schaffhausen, B. S., Rudd, C. E., and Cantley, L. C., 1994, Identification of two SH3-binding motifs in the regulatory subunit of phosphatidylinositol 3-kinase, J. Biol. Chem. 269: 1927–1933.PubMedGoogle Scholar
  80. 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: 1021–1029.PubMedCrossRefGoogle Scholar
  81. Karnitz, L. M., Sutor, S. L., and Abraham, R. T., 1994, The Src-family kinase, Fyn, regulates the activation of phosphatidylinositol 3-kinase in an interleukin 2-responsive T cell line, J. Exp. Med. 179: 1799–1808.PubMedCrossRefGoogle Scholar
  82. Kavanaugh, W. M., and Williams, L. T., 1994, An alternative to SH2 domains for binding tyrosinephosphorylated proteins, Science 266: 1862–1865.PubMedCrossRefGoogle Scholar
  83. Kazlauskas, A., and Cooper, J. A., 1989, Autophosphorylation of the PDGF receptor in the kinase insert region regulates interactions with cell proteins, Cell 58: 1121–1133.PubMedCrossRefGoogle Scholar
  84. Kazlauskas, A., and Cooper, J. A., 1990, Phosphorylation of the PDGF receptor beta subunit creates a tight binding site for phosphatidylinositol 3 kinase, EMBO J. 9: 3279–3286.PubMedGoogle Scholar
  85. Kazlauskas, A., Kashishian, A., Cooper, J. A., and Valius, M., 1992, GTPase-activating protein and phosphatidylinositol 3-kinase bind to distinct regions of the platelet-derived growth factor receptor beta subunit, Mol. Cell. Biol. 12: 2534–2544.PubMedGoogle Scholar
  86. Kelly, K L., and Ruderman, N. B., 1993, Insulin-stimulated phosphatidyinositol 3-kinase. Association with a 185-kDa tyrosine-phosphorylated protein (IRS-1) and localization in a low density membrane vesicle, J. Biol. Chem. 268: 4391–4398.PubMedGoogle Scholar
  87. Kim, H. H., Sierke, S. L., and Koland, J. G., 1994, Epidermal growth factor-dependent association of phosphatidylinositol 3-kinase with the erbB3 gene product, j Biol. Chem. 269: 24747–24755.PubMedGoogle Scholar
  88. Kimura, K., Hattori, S., Kabuyama, Y., Shizawa, Y, Takayanagi, J., Nakamura, S., Toki, S., Matsuda, Y, Onodera, K., and Fukui, Y, 1994, Neurite outgrowth of PC12 cells is suppressed by wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase, J. Biol. Chem. 269: 18961–18967.PubMedGoogle Scholar
  89. Klippel, A., Escobedo, J. A., Fantl, W.J., and Williams, L. T., 1992, The C-terminal SH2 domain of p85 accounts for the high affinity and specificity of the binding of phosphatidylinositol 3-kinase to phosphorylated platelet-derived growth factor beta receptor, Mol. Cell. Biol. 12: 1451–1459.PubMedGoogle Scholar
  90. Klippel, A., Escobedo, J. A., Hu, Q., and Williams, L. T., 1993, A region of the 85-kilodalton (kDa) subunit of phosphatidylinositol 3-kinase binds the 110-kDa catalytic subunit in vivo, Mol. Cell. Biol. 13: 5560–5566.PubMedGoogle Scholar
  91. Klippel, A., Escobedo, J. A., Hirano, M., and Williams, L. T., 1994, The interaction of small domains between the subunits of phosphatidylinositol 3-kinase determines enzyme activity, Mol. Cell. Biol. 14: 2675–2685.PubMedCrossRefGoogle Scholar
  92. Knighton, D. R., Zheng, J. H., Ten, E. L., Ashford, V. A., Xuong, N. H., Taylor, S. S., and Sowadski, J. M., 1991, Crystal structure of the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase [see comments], Science 253: 407–414.PubMedCrossRefGoogle Scholar
  93. Kodaki, T., Woscholski, R., Hallberg, B., Rodriguez, V. P., Downward, J., and Parker, P. J., 1994, The activation of phosphatidylinositol 3-kinase by Ras, Cura. Biol. 4: 798–806.Google Scholar
  94. Kotani, K., Yonezawa, K., Hara, K., Ueda, H., Kitamura, Y, Sakaue, H., Ando, A., Chavanieu, A., Calas, B., Grigorescu, F., Nishiyama, M., Waterfield, M. D., and Kasuga, M., 1994, Involvement of phosphoinositide 3-kinase in insulin-or IGF-1-induced membrane ruffling, EMBO J. 13: 2313 2321.Google Scholar
  95. Koyama, S., Yu, H., Dalgarno, D. C., Shin, T. B., Zydowsky, L. D., and Schreiber, S. L., 1993, Structure of the PI3K SH3 domain and analysis of the SH3 family, Cell 72: 945–952.PubMedCrossRefGoogle Scholar
  96. Lam, K., Carpenter, C. L., Ruderman, N. B., Friel, J. C., and Kelly, K. L., 1994, The phosphatidylinositol 3-kinase serine kinase phosphorylates IRS-1. Stimulation by insulin and inhibition bywortmannin, J. Biol. Chem. 269: 20648–20652.PubMedGoogle Scholar
  97. Lamphere, L., Carpenter, C. L., Sheng, Z. F., Kallen, R. G., and Lienhard, G. E., 1994, Activation of PI 3-kinase in 3T3–L1 adipocytes by association with insulin receptor substrate-1, Am. j Physiol. 266: E486 — E494.PubMedGoogle Scholar
  98. Lee, C. H., Kominos, D., Jacques, S., Margolis, B., Schlessinger, J., Shoelson, S. E., and Kuriyan, J., 1994, Crystal structures of peptide complexes of the amino-terminal SH2 domain of the Syp tyrosine phosphatase, Structure 2: 423–438.PubMedCrossRefGoogle Scholar
  99. Lim, W. A., Richards, F. M., and Fox, R. 0., 1994, Structural determinants of peptide-binding orientation and of sequence specificity in SH3 domains, Nature 372: 375–379.Google Scholar
  100. Ling, L. E., Druker, B.J., Cantley, L. C., and Roberts, T. M., 1992, Transformation-defective mutants of polyomavirus middle T antigen associate with phosphatidylinositol 3-kinase (PI 3-kinase) but are unable to maintain wild-type levels of PI 3-kinase products in intact cells, J Virol. 66: 1702–1708.PubMedGoogle Scholar
  101. Liu, X., Marengere, L. E., Koch, C. A., and Pawson, T., 1993, The v-Src SH3 domain binds phosphatidylinositol 3’ kinase, Mol. Cell. Biol. 13: 5225–5232.PubMedGoogle Scholar
  102. Macara, I. G., Marinetti, G. V., and Balduzzi, P. C., 1984, Transforming protein of avian sarcoma virus UR2 is associated with phosphatidylinositol kinase activity: Possible role in tumorigenesis, Proc. Natl. Acad. Sci. USA 81: 2728–2732.PubMedCrossRefGoogle Scholar
  103. Marshall, C. J., 1994, MAP kinase kinase kinase, MAP kinase kinase, and MAP kinase, Curr Opin. Gen. Dev. 4: 82–89.CrossRefGoogle Scholar
  104. Miller, E. S., and Ascoli, M., 1990, Anti-phosphotyrosine immunoprecipitation of phosphatidylinositol 3’-kinase activity in different cell types after exposure to epidermal growth factor, Biochem. Biophys. Res. Commun. 173: 289–295.PubMedCrossRefGoogle Scholar
  105. Ming, X. F., Burgering, B. M., Wennstrom, S., Claesson, W. L., Heldin, C. H., Bos, J. L., Kozma, S. C., and Thomas, G., 1994, Activation of p70/p85 S6 kinase by a pathway independent of p2lras, Nature 371: 426–429.PubMedCrossRefGoogle Scholar
  106. Mischak, H., Goodnight, J. A., Kolch, W., Martiny, B. G., Schaechtle, C., Kazanietz, M. G., Blumberg, P. M., Pierce, J. H., and Mushinski, J. E, 1993, Overexpression of protein kinase C-delta and -epsilon in NIH 3T3 cells induces opposite effects on growth, morphology, anchorage dependence, and tumorigenicity, J. Biol. Chem. 268: 6090–6096.PubMedGoogle Scholar
  107. Monfar, M., Lemon, K. P., Grammer, T. C., Cheatham, L., Chung, J., Vlahos, C. J., and Blenis, J., 1995, Activation of pp70/85 S6 kinases in interleukin-2-responsive lymphoid cells is mediated by phosphatidylinositol 3-kinase and inhibited by cyclic AMP, Mol. Cell. Biol. 15: 326–337.PubMedGoogle Scholar
  108. Morgan, S. J., Smith, A. D., and Parker, P. J., 1990, Purification and characterization of bovine brain type I phosphatidylinositol kinase, Eur. J Biochem. 191: 761–767.CrossRefGoogle Scholar
  109. Myers, M.J., Backer, J. M., Sun, X.J., Shoelson, S., Hu, P., Schlessinger,J., Yoakim, M., Schaffhausen, B., and White, M. E, 1992, IRS-1 activates phosphatidylinositol 3’-kinase by associating with src homology 2 domains of p85, Proc. Natl. Acad. Sci. USA 89: 10350–10354.Google Scholar
  110. Nakanishi, H., Brewer, K. A., and Exton, J. H.,1993, Activation of the zeta isozyme of protein kinase C by phosphatidylinositol 3,4,5-trisphosphate, J Biol. Chem. 268:13–16.Google Scholar
  111. Nobes, C. D., and Hall, A., 1995, Rho, Rac, and CDC42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia, Cell 81: 53–62.PubMedCrossRefGoogle Scholar
  112. Okada, T., Kawano, Y, Sakakibara, T., Hazeki, O., and Ui, M., 1994a, Essential role of phosphatidylionositol 3-kinase in insulin-induced glucose transport and antilipolysis in rat adipocytes. Studies with a selective inhibitor wortmannin, J Biol. Chem. 269: 3568–3573.Google Scholar
  113. Okada, T., Sakuma, L., Fukui, Y., Hazeki, O., and Ui, M., 1994b, Blockage of chemotactic peptide-induced stimulation of neutrophils by wortmannin as a result of selective inhibition of phosphatidylinositol 3-kinase, J. Biol. Chem. 269: 3563–3567.PubMedGoogle Scholar
  114. Otsu, M., Hiles, I., Gout, I., Fry, M. J., Ruiz, L. F., Panayotou, G., Thompson, A., Dhand, R., Hsuan, J., Totty, N., Smith, A. D., Morgan, S. J., Courtneidge, S. A., Parker, P.J., and Waterfield, M. D., 1991, Characterization of two 85 kd proteins that associate with receptor tyrosine kinases, middleT/pp60c-src complexes, and PI3-kinase, Cell 65: 91–104.PubMedCrossRefGoogle Scholar
  115. Overduin, M., Rios, C. B., Mayer, B. J., Baltimore, D., and Cowburn, D., 1992, Three-dimensional solution structure of the src homology 2 domain of c-abl, Cell 70: 697–704.PubMedCrossRefGoogle Scholar
  116. Pallas, D. C., Cherington, V., Morgan, W., DeAnda, J., Kaplan, D., Schaffhausen, B., and Roberts, T. M., 1988, Cellular proteins that associate with the middle and small T antigens of polyomavirus, J. Virol. 62: 3934–3940.PubMedGoogle Scholar
  117. Pallas, D. C., Shahrik, L. K., Martin, B. L., Jaspers, S., Miller, T. B., Brautigan, D. L., and Roberts, T. M., 1990, Polyoma small and middle T antigens and SV40 small t antigen form stable complexes with protein phosphatase 2A, Cell 60: 167–176.PubMedCrossRefGoogle Scholar
  118. Panayotou, G., Gish, G., End, P., Truong, O., Gout, I., Dhand, R., Fry, M. J., Hiles, I., Pawson, T., and Waterfield, M. D., 1993, Interactions between SH2 domains and tyrosine-phosphorylated platelet-derived growth factor beta-receptor sequences: Analysis of kinetic parameters by a novel biosensor-based approach, Mol. Cell. Biol. 13: 3567–3576.PubMedGoogle Scholar
  119. Pascal, S. M., Singer, A. U., Gish, G., Yamazaki, T., Shoelson, S. E., Pawson, T., Kay, L. E., and Forman, K. J., 1994, Nuclear magnetic resonance structure of an SH2 domain of phospholipase C-gamma 1 complexed with a high affinity binding peptide, Cell 77: 461–472.PubMedCrossRefGoogle Scholar
  120. Piccione, E., Case, R. D., Domchek, S. M., Hu, P., Chaudhuri, M., Backer, J. M., Schlessinger, J., and Shoelson, S. E., 1993, Phosphatidylinositol 3-kinase p85 SH2 domain specificity defined by direct phosphospeptide/SH2 domain binding, Biochemistry 32: 3197–3202.PubMedCrossRefGoogle Scholar
  121. Pignataro, O. P., and Ascoli, M., 1990, Studies with insulin and insulin-like growth factor-I show that the increased labeling of phosphatidylinositol-3,4-bisphosphate is not sufficient to elicit the diverse actions of epidermal growth factor on MA-10 Leydig tumor cells, Mol. Endocrinol. 4: 758–765.PubMedCrossRefGoogle Scholar
  122. Pleiman, C. M., Clark, M. R., Gauen, L. K., Winitz, S., Coggeshall, K. M., Johnson, G. L., Shaw, A. S., and Cambier, J. C., 1993, Mapping of sites on the Src family protein tyrosine kinases p55blk, p59fyn, and p561yn which interact with the effector molecules phospholipase C-gamma 2, microtubuleassociated protein kinase, GTPase-activating protein, and phosphatidylinositol 3-kinase, Mol. Cell. Biol. 13: 5877–5887.PubMedGoogle Scholar
  123. Pleiman, C. M., Hertz, W. M., and Cambier, J. C., 1994, Activation of phosphatidylinositol-3’ kinase by Src-family kinase SH3 binding to the p85 subunit, Science 263: 1609–1612.PubMedCrossRefGoogle Scholar
  124. Prasad, K. V., Janssen, O., Kapeller, R., Raab, M., Cantley, L. C., and Rudd, C. E., 1993a, Src-homology 3 domain of protein kinase p59fyn mediates binding to phosphatidylinositol 3-kinase in T cells, Proc. Natl. Acad. Sci. USA 90: 7366–7370.PubMedCrossRefGoogle Scholar
  125. Prasad, K. V., Kapeller, R, Janssen, O., Repke, H., Duke, C. J., Cantley, L. C., and Rudd, C. E., 1993b, Phosphatidylinositol (PI) 3-kinase and PI 4-kinase binding to the CD4—p561ack complex: The p561ck SH3 domain binds to PI 3-kinase but not PI 4-kinase, Mol. Cell. Biol. 13: 7708–7717.PubMedGoogle Scholar
  126. Prigent, S. A., and Gullick, W. J., 1994, Identification of c-erbB-3 binding sites for phosphatidylinositol 3’-kinase and SHC using an EGF receptor/c-erbB-3 chimera, EMBO J. 13: 2831–2841.PubMedGoogle Scholar
  127. Raffioni, S., and Bradshaw, R. A., 1992, Activation of phosphatidylinositol 3-kinase by epidermal growth factor, basic fibroblast growth factor, and nerve growth factor in PC12 pheochromocytoma cells, Proc. Natl. Acad. Sci. USA 89: 9121–9125.PubMedCrossRefGoogle Scholar
  128. Reedijk, M., Liu, X. Q., and Pawson, T., 1990, Interactions of phosphatidylinositol kinase, GTPaseactivating protein (GAP), and GAP-associated proteins with the colony-stimulating factor 1 receptor, Mol. Cell. Biol. 10: 5601–5608.PubMedGoogle Scholar
  129. Reedijk, M., Liu, X., van der Geer, P., Letwin, K., Waterfield, M. D., Hunter, T., and Pawson, T., 1992, Tyr721 regulates specific binding of the CSF 1 receptor kinase insert to PI 3’-kinase SH2 domains: A model for SH2-mediated receptor—target interactions, EMBO J 11: 1365–1372.PubMedGoogle Scholar
  130. Rickles, R. J., Botfield, M. C., Weng, Z., Taylor, J. A., Green, O. M., Brugge, J. S., and Zoller, M. J., 1994, Identification of Src, Fyn, Lyn, PI3K and Abl SH3 domain ligands using phage display libraries, EMBO J. 13: 5598–5604.PubMedGoogle Scholar
  131. 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
  132. Roche, S., Koegl, M., and Courtneidge, S. A.,1994, The phosphatidylinositol 3-kinase alpha is required for DNA synthesis induced by some, but not all, growth factors, Proc. Natl. Sci. USA 91: 9185–9189.Google Scholar
  133. Rodriguez-Viciana, P., Warne, P. H., Dhand, R., Vanhaesebroeck, B., Gout, I., Fry, M. J., Waterfield, M. D., and Downward, J., 1994, Phosphatidylinositol-3-OH kinase as a direct target of Ras, Nature 370: 527–532.PubMedCrossRefGoogle Scholar
  134. Ruderman, N. B., Kapeller, R, White, M. E, and Cantley, L. C., 1990, Activation of phosphatidylinositol 3-kinase by insulin, Proc. Natl. Acad. Sci. USA 87: 1411–1415.PubMedCrossRefGoogle Scholar
  135. Sanchez, M. V., Goldfine, I. D., Vlahos, C. J., and Sung, C. K., 1994, Role of phosphatidylinositol-3kinase in insulin receptor signaling: Studies with inhibitor, LY294002, Biochem. Biophys. Res. Commun. 204: 446–452.CrossRefGoogle Scholar
  136. Satoh, T., Fantl, W. J., Escobedo, J. A., Williams, L. T., and Kaziro, Y, 1993, Platelet-derived growth factor receptor mediates activation of ras through different signaling pathways in different cell types, Mol. Cell. Biol. 13: 3706–3713.PubMedGoogle Scholar
  137. Schu, P. V., Takegawa, K, Fry, M.J., Stack, J. H., Waterfield, M. D., and Emr, S. D., 1993, Phosphatidylinositol 3-kinase encoded by yeast VPS34 gene essential for protein sorting, Science 260: 88–91.PubMedCrossRefGoogle Scholar
  138. 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: 17809–17815.PubMedGoogle Scholar
  139. Serunian, L. A., Auger, K. R., Roberts, T. M., and Cantley, L. C., 1990, Production of novel polyphosphoinositides in vivo is linked to cell transformation by polyomavirus middle T antigen, J. Virol. 64: 4718–4725.PubMedGoogle Scholar
  140. Shepherd, P. R., Nave, B. T., and Siddle, K., 1995, Insulin stimulation of glycogen synthesis and glycogen synthase activity is blocked by wortmannin and rapamycin in 3T3-LI adipocytes: Evidence for the involvement of phosphoinositide 3-kinase and p70 ribosomal protein-S6 kinase, Biochem. J. 305: 25–28.PubMedGoogle Scholar
  141. 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: 8108–8114.PubMedGoogle Scholar
  142. Shinjo, K., Koland, J. G., Hart, M.J., Narasimhan, V., Johnson, D. I., Evans, T., and Cerione, R. A., 1990, Molecular cloning of the gene for the human placental GTP-binding protein GP (G25K): Identification of this GTP-binding protein as the human homolog of the yeast cell-division-cycle protein CDC42, Proc. Natl. Acad. Sci. USA 87: 9853–9857.PubMedCrossRefGoogle Scholar
  143. Singh, S. S., Chauhan, A., Brockerhoff, H., and Chauhan, V. P., 1993, Activation of protein kinase C by phosphatidylinositol 3,4,5-trisphosphate, Biochem. Biophys. Res. Commun. 195: 104–112.PubMedCrossRefGoogle Scholar
  144. Sjolander, A., and Lapetina, E. G., 1992, Agonist-induced association of the p2lras GTPase-activating protein with phosphatidylinositol 3-kinase, Biochem. Biophys. Res. Commun. 189: 1503–1508.PubMedCrossRefGoogle Scholar
  145. Sjolander, A., Yamamoto, K., Huber, B. E., and Lapetina, E. G., 1991, Association of p2lras with phosphatidylinositol 3-kinase, Proc. Natl. Acad. Sci. USA 88: 7908–7912.PubMedCrossRefGoogle Scholar
  146. 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
  147. Sliwkowski, M. X., Schaefer, G., Akita, R. W., Lofgren, J. A., Fitzpatrick, V. D., Nuijens, A., Fendly, B. M., Cerione, R. A., Vandlen, R. L., and Carraway, K. L., III, 1994, Coexpression of erbB2 and erbB3 proteins reconstitutes a high affinity receptor for heregulin, J. Biol. Chem. 269: 14661–14665.PubMedGoogle Scholar
  148. Soltoff, S. P., Carraway, K. L., III, Prigent, S. A., Gullick, W. G., and Cantley, L. C., 1994, ErbB3 is involved in activation of phosphatidylinositol 3-kinase by epidermal growth factor, Mol. Cell. Biol. 14: 3550–3558.PubMedGoogle Scholar
  149. Songyang, Z., Shoelson, S. E., Chaudhuri, M., Gish, G., Pawson, T., Haser, W. G., King, F., Roberts, T., Ratnofsky, S., Lechleider, R.J., Neel, B. G., Birge, R. B., Fajardo, J. E., Chou, M. M., Hanafusa, H., Schaffhausen, B., and Cantley, L. C., 1993, SH2 domains recognize specific phosphopeptide sequences, Celi 72: 767–778.CrossRefGoogle Scholar
  150. Stack, J. H., and Emr, S. D., 1994, Vps34p required for yeast vacuolar protein sorting is a multiple specificity kinase that exhibits both protein kinase and phosphatidylinositol-specific PI 3-kinase activities, J. Biol. Chem. 269: 31552–31562.PubMedGoogle Scholar
  151. Stephens, L. R., Hughes, K. T., and Irvine, R. F., 1991, Pathway of phosphatidylinositol(3,4,5)trisphosphate synthesis in activated neutrophils, Nature 351: 33–39.PubMedCrossRefGoogle Scholar
  152. Stephens, L., Jackson, T., and Hawkins, P. T., 1993a, Synthesis of phosphatidylinositol 3,4,5trisphosphate in permeabilized neutrophils regulated by receptors and G-proteins, J. Biol. Chem. 268: 17162–17172.PubMedGoogle Scholar
  153. Stephens, L. R., Jackson, T. R., and Hawkins, P. T., 1993b, Agonist-stimulated synthesis of phosphatidylinositol (3,4,5)-trisphosphate: A new intracellular signalling system? Biochim. Biophys. Acta 1179: 27–75.PubMedCrossRefGoogle Scholar
  154. Stephens, L., Smrcka, A., Cooke, F. T., Jackson, T. R., Sternweis, P. C., and Hawkins, P. T., 1994, A novel phosphoinositide 3 kinase activity in myeloid-derived cells is activated by G protein beta gamma subunits, Cell 77: 83–93.PubMedCrossRefGoogle Scholar
  155. Sugimoto, Y, and Erikson, R. L., 1985, Phosphatidylinositol kinase activities in normal and Rous sarcoma virus-transformed cells, Mol. Cell. Biol. 5: 3194–3198.PubMedGoogle Scholar
  156. Sultan, C., Breton, M., Mauco, G., Grondin, P., Plantavid, M., and Chap, H., 1990, The novel inositol lipid phosphatidylinositol 3,4-bisphosphate is produced in human blood platelets upon thrombin stimulation, Biochem. J 269: 831–834.PubMedGoogle Scholar
  157. Sun, X.J., Rothenberg, P., Kahn, C. R., Backer, J. M., Araki, E., Wilden, P. A., Cahill, D. A., Goldstein, B. J., and White, M. E, 1991, Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein, Nature 352: 73–77.PubMedCrossRefGoogle Scholar
  158. Sun, X. J., Crimmins, D. L., Myers, M. J., Miralpeix, M., and White, M. F., 1993, Pleiotropic insulin signals are engaged by multisite phosphorylation of IRS-1, Mol. Cell. Biol. 13: 7418–7428.PubMedGoogle Scholar
  159. Sung, C. K., and Goldfine, I. D., 1992, Phosphatidylinositol-3-kinase is a nontyrosine phosphorylated member of the insulin receptor signalling complex, Biochem. Biophys. Res. Commun. 189: 1024–1030.PubMedCrossRefGoogle Scholar
  160. Susa, M., Keeler, M., and Varticovski, L., 1992, Platelet-derived growth factor activates membrane-associated phosphatidylinositol 3-kinase and mediates its translocation from the cytosol. Detection of enzyme activity in detergent solubilized cell extracts, J. Biol. Chem. 267: 22951–22956.PubMedGoogle Scholar
  161. Talmage, D. A., Freund, R., Young, A. T., Dahl, J., Dawe, C. J., and Benjamin, T. L., 1989, Phosphorylation of middle T by pp60c-src: A switch for binding of phosphatidylinositol 3-kinase and optimal tumorigenesis, Cell 59: 55–65.PubMedCrossRefGoogle Scholar
  162. Toker, A., Meyer, M., Reddy, K. K, Falck, J. R., Aneja, R., Aneja, S., Parra, A., Burns, D. J., Ballas, L. M., and Cantley, L. C., 1994, Activation of protein kinase C family members by the novel polyphosphoinositides Ptdlns-3,4-P2 and Ptdlns-3,4,5-P3, J Biol. Chem. 269: 32358–32367.PubMedGoogle Scholar
  163. Tolias, K. F., Cantley, L. C., and Carpenter, C. L., 1995, Rho family GTPases bind to phosphoinositide kinases, J. Biol. Chem. 270: 17656–17659.PubMedCrossRefGoogle Scholar
  164. Valius, M., and Kazlauskas, A., 1993, Phospholipase C-gamma 1 and phosphatidylinositol 3 kinase are the downstream mediators of the PDGF receptor’s mitogenic signal, Cell 73: 321–334.PubMedCrossRefGoogle Scholar
  165. Varticovski, L., Daley, G. Q., Jackson, P., Baltimore, D., and Cantley, L. C., 1991, Activation of phospha- tidylinositol 3-kinase in cells expressing abl oncogene variants, Mol. Cell. Biol. 11: 1107–1113.PubMedGoogle Scholar
  166. Varticovski, L., Harrison, F. D., Keeler, M. L., and Susa, M., 1994, Role of PI 3-kinase in mitogenesis, Biochim. Biophys. Acta 1226: 1–11.PubMedCrossRefGoogle Scholar
  167. Vemuri, G. S., and Rittenhouse, S. E., 1994, Wortmannin inhibits serum-induced activation of phosphoinositide 3-kinase and proliferation of CHRF-288 cells, Biochem. Biophys. Res. Commun. 202: 1619–1623.PubMedCrossRefGoogle Scholar
  168. Vogel, L. B., and Fujita, D.J., 1993, The SH3 domain of p561ck is involved in binding to phosphatidylinositol 3’-kinase from T lymphocytes, Mol. Cell. Biol. 13: 7408–7417.PubMedGoogle Scholar
  169. Wages, D. S., Keefer, J., Rall, T. B., and Weber, M. J., 1992, Mutations in the SH3 domain of the src oncogene which decrease association of phosphatidylinositol 3’-kinase activity with pp60v-src and alter cellular morphology, j Viral. 66: 1866–1874.Google Scholar
  170. Waksman, G., Kominos, D., Robertson, S. C., Pant, N., Baltimore, D., Birge, R. B., Cowburn, D., Hanafusa, H., Mayer, B. J., Overduin, M., Resh, M. D., Rios, C. B., Silverman, L., and Kuriyan, J., 1992, Crystal structure of the phosphotyrosine recognition domain SH2 of v-src complexed with tyrosine-phosphorylated peptides [see comments], Nature 358: 646–653.PubMedCrossRefGoogle Scholar
  171. Waksman, G., Shoelson, S. E., Pant, N., Cowburn, D., and Kuriyan, J., 1993, Binding of a high affinity phosphotyrosyl peptide to the Src SH2 domain: Crystal structures of the complexed and peptide-free forms, Cell 72: 779–790.PubMedCrossRefGoogle Scholar
  172. Welsh, G. I., Foulstone, E.J., Young, W. S., Tavare, J. M., and Proud, C. G., 1994, Wortmannin inhibits the effects of insulin and serum on the activities of glycogen synthase kinase-3 and mitogenactivated protein kinase, Biochem. J. 303: 15–20.PubMedGoogle Scholar
  173. Wennstrom, S., Hawkins, P., Cooke, F., Hara, K., Yonezawa, K., Kasuga, M., Jackson, T., Claesson, W. L., and Stephens, L., 1994a, Activation of phosphoinositide 3-kinase is required for PDGF-stimulated membrane ruffling, Curr. Biol. 4: 385–393.PubMedCrossRefGoogle Scholar
  174. Wennstrom, S., Siegbahn, A., Yokote, K., Arvidsson, A. K, Heldin, C. H., Mori, S., and Claesson, W. L., 1994b, Membrane ruffling and chemotaxis transduced by the PDGF beta-receptor require the binding site for phosphatidylinositol 3’ kinase, Oncogene 9: 651–660.PubMedGoogle Scholar
  175. White, M. F., and Kahn, C. R., 1994, The insulin signaling system, J. Biol. Chem. 269: 1–4.PubMedGoogle Scholar
  176. White, M. F., Maron, R., and Kahn, C. R., 1985, Insulin rapidly stimulates tyrosine phosphorylation of a Mr-185,000 protein in intact cells, Nature 318: 183–186.PubMedCrossRefGoogle Scholar
  177. 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: 239–242.PubMedCrossRefGoogle Scholar
  178. Whitman, M., Kaplan, D., Roberts, T., and Cantley, L., 1987, Evidence for two distinct phosphatidyl- inositol kinases in fibroblasts. Implications for cellular regulation, Biochem. J 247: 165–174.PubMedGoogle Scholar
  179. 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: 644646.Google Scholar
  180. Wittekind, M., Mapelli, C., Farmer, B., Suen, K. L., Goldfarb, V., Tsao, J., Lavoie, T., Barbacid, M., Meyers, C. A., and Mueller, L., 1994, Orientation of peptide fragments from Sos proteins bound to the N-terminal SH3 domain of Grb2 determined by NMR spectroscopy, Biochemistry 33: 13531–13539.PubMedCrossRefGoogle Scholar
  181. Wong, K., and Cantley, L. C., 1994, Cloning and characterization of a human phosphatidylinositol 4-kinase, J. Biol. Chem. 269: 28878–28884.PubMedGoogle Scholar
  182. Yamamoto, K., Graziani, A., Carpenter, C., Cantley, L. C., and Lapetina, E. G., 1990, A novel pathway for the formation of phosphatidylinositol 3,4-bisphosphate. Phosphorylation of phosphatidylinositol 3-monophosphate by phosphatidylinositol-3-monophosphate 4-kinase, J. Biol. Chem. 265: 220862 2089.Google Scholar
  183. Yamauchi, K., Holt, K., and Pessin, J. E., 1993, Phosphatidylinositol 3-kinase functions upstream of Ras and Raf in mediating insulin stimulation of c-fos transcription, J. Biol. Chem. 268: 14597–14600.PubMedGoogle Scholar
  184. Yano, H., Nakanishi, S., Kimura, K., Hanai, N., Saitoh, Y, Fukui, Y., Nonomura, Y, and Matsuda, Y., 1993, Inhibition of histamine secretion by wortmannin through the blockade of phosphatidylinositol 3-kinase in RBL-2H3 cells, J. Biol. Chem. 268: 25846–25856.PubMedGoogle Scholar
  185. Yeh, J. I., Gulve, E. A., Rameh, L., and Birnbaum, M. J., 1995, The effects of wortmannin on rat skeletal muscle. Dissociation of signaling pathways for insulin-and contraction-activated hexose transport, J Biol. Chem. 270: 2107–2111.PubMedCrossRefGoogle Scholar
  186. Yoakim, M., Hou, W., Liu, Y, Carpenter, C. L., Kapeller, R., and Schaffhausen, B. S., 1992, Interactions of polyomavirus middle T with the SH2 domains of the pp85 subunit of phosphatidylinositol-3kinase, J. Virol. 66: 5485–5491.PubMedGoogle Scholar
  187. Yonezawa, K., Ueda, H., Hara, K, Nishida, K., Ando, A., Chavanieu, A., Matsuba, H., Shii, K, Yokono, K, Fukui, Y., Calas, B., Grigorescu, E, Dhand, R., Gout, I., Otsu, M., Waterfield, M. D., and Kasuga, M., 1992a, Insulin-dependent formation of a complex containing an 85-kDa subunit of phosphatidylinositol 3-kinase and tyrosine-phosphorylated insulin receptor substrate 1, J. Biol. Chem. 267: 25958–25965.PubMedGoogle Scholar
  188. Yonezawa, K., Yokono, K., Shii, K., Ogawa, W., Ando, A., Hara, K., Baba, S., Kaburagi, Y., Yamamoto, H. R., Momomura, K., Kadowaki, T., and Kasuga, M., 1992b, In vitro association of phosphatidylinositol 3-kinase activity with the activated insulin receptor tyrosine kinase, J. Biol. Chem. 267: 440–446.PubMedGoogle Scholar
  189. Yoshida, S., Ohya, Y, Goeb1, M., Nakano, A., and Anraku, Y., 1994, A novel gene, STT4, encodes a phosphatidylinositol 4-kinase in the PKC1 protein kinase pathway of Saccharomyces cerevisiae, J. Biol. Chem. 269: 1166–1172.PubMedGoogle Scholar
  190. Zhang, J., King, W. G., Dillon, S., Hall, A., Feig, L., and Rittenhouse, S. E., 1993, Activation of platelet phosphatidylinositide 3-kinase requires the small GTP-binding protein Rho, j Biol. Chem. 268: 22251–22254.PubMedGoogle Scholar
  191. Zhang, J., Zhang, J., Benovic, J. L., Sugai, M., Wetzker, R., Gout, I., and Rittenhouse, S. E., 1995, Sequestration of a G-protein ßry subunit or ADP-ribosylation of rho can inhibit thrombin-induced activation of platelet phosphoinositide 3-kinases, J. Biol. Chem. 270: 6589–6594.PubMedCrossRefGoogle Scholar
  192. Zheng, Y, Hart, M. J., Shinjo, K., Evans, T., Bender, A., and Cerione, R. A., 1993, Biochemical comparisons of the Saccharomyces cerevisiae Bem2 and Bem3 proteins. Delineation of a limit Cdc42 GTPase-activating protein domain, J. Biol. Chem. 268: 24629–24634.PubMedGoogle Scholar
  193. Zheng, Y., Bagrodia, S., and Cerione, R. A., 1994, Activation of phosphoinositide 3-kinase activity by Cdc42Hs binding to p85, J. Biol. Chem. 269: 18727–18730.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1996

Authors and Affiliations

  • Brian C. Duckworth
    • 1
  • Lewis C. Cantley
    • 2
  1. 1.Department of PhysiologyTufts UniversityBostonUSA
  2. 2.Division of Signal Transduction, Beth Israel Hospital, and Department of Cell BiologyHarvard Medical SchoolBostonUSA

Personalised recommendations