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Philosophical Transactions of the Royal Society B: Biological Sciences logoLink to Philosophical Transactions of the Royal Society B: Biological Sciences
. 1999 Feb 28;354(1382):485–495. doi: 10.1098/rstb.1999.0399

The Croonian Lecture 1998. Identification of a protein kinase cascade of major importance in insulin signal transduction.

P Cohen 1
PMCID: PMC1692513  PMID: 10212493

Abstract

Diabetes affects 3% of the European population and 140 million people worldwide, and is largely a disease of insulin resistance in which the tissues fail to respond to this hormone. This emphasizes the importance of understanding how insulin signals to the cell's interior. We have recently dissected a protein kinase cascade that is triggered by the formation of the insulin 'second messenger' phosphatidylinositide (3,4,5) trisphosphate (PtdIns (3,4,5)P3) and which appears to mediate many of the metabolic actions of this hormone. The first enzyme in the cascade is termed 3-phosphoinositide-dependent protein kinase-1 (PDK1), because it only activates protein kinase B (PKB), the next enzyme in the pathway, in the presence of PtdIns (3,4,5)P3. PKB then inactivates glycogen synthase kinase-3 (GSK3). PDK1, PKB and GSK3 regulate many physiological events by phosphorylating a variety of intracellular proteins. In addition, PKB plays an important role in mediating protection against apoptosis by survival factors, such as insulin-like growth factor-1.

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Selected References

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  1. Ahmed N. N., Grimes H. L., Bellacosa A., Chan T. O., Tsichlis P. N. Transduction of interleukin-2 antiapoptotic and proliferative signals via Akt protein kinase. Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3627–3632. doi: 10.1073/pnas.94.8.3627. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Alessi D. R., Andjelkovic M., Caudwell B., Cron P., Morrice N., Cohen P., Hemmings B. A. Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J. 1996 Dec 2;15(23):6541–6551. [PMC free article] [PubMed] [Google Scholar]
  3. Alessi D. R., Caudwell F. B., Andjelkovic M., Hemmings B. A., Cohen P. Molecular basis for the substrate specificity of protein kinase B; comparison with MAPKAP kinase-1 and p70 S6 kinase. FEBS Lett. 1996 Dec 16;399(3):333–338. doi: 10.1016/s0014-5793(96)01370-1. [DOI] [PubMed] [Google Scholar]
  4. Alessi D. R., Cuenda A., Cohen P., Dudley D. T., Saltiel A. R. PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo. J Biol Chem. 1995 Nov 17;270(46):27489–27494. doi: 10.1074/jbc.270.46.27489. [DOI] [PubMed] [Google Scholar]
  5. Alessi D. R., Deak M., Casamayor A., Caudwell F. B., Morrice N., Norman D. G., Gaffney P., Reese C. B., MacDougall C. N., Harbison D. 3-Phosphoinositide-dependent protein kinase-1 (PDK1): structural and functional homology with the Drosophila DSTPK61 kinase. Curr Biol. 1997 Oct 1;7(10):776–789. doi: 10.1016/s0960-9822(06)00336-8. [DOI] [PubMed] [Google Scholar]
  6. Alessi D. R., James S. R., Downes C. P., Holmes A. B., Gaffney P. R., Reese C. B., Cohen P. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol. 1997 Apr 1;7(4):261–269. doi: 10.1016/s0960-9822(06)00122-9. [DOI] [PubMed] [Google Scholar]
  7. Alessi D. R., Kozlowski M. T., Weng Q. P., 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 Jan 15;8(2):69–81. doi: 10.1016/s0960-9822(98)70037-5. [DOI] [PubMed] [Google Scholar]
  8. Andjelković M., Alessi D. R., Meier R., Fernandez A., Lamb N. J., Frech M., Cron P., Cohen P., Lucocq J. M., Hemmings B. A. Role of translocation in the activation and function of protein kinase B. J Biol Chem. 1997 Dec 12;272(50):31515–31524. doi: 10.1074/jbc.272.50.31515. [DOI] [PubMed] [Google Scholar]
  9. Andjelković M., Jakubowicz T., Cron P., Ming X. F., Han J. W., Hemmings B. A. Activation and phosphorylation of a pleckstrin homology domain containing protein kinase (RAC-PK/PKB) promoted by serum and protein phosphatase inhibitors. Proc Natl Acad Sci U S A. 1996 Jun 11;93(12):5699–5704. doi: 10.1073/pnas.93.12.5699. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Badger A. M., Bradbeer J. N., Votta B., Lee J. C., Adams J. L., Griswold D. E. Pharmacological profile of SB 203580, a selective inhibitor of cytokine suppressive binding protein/p38 kinase, in animal models of arthritis, bone resorption, endotoxin shock and immune function. J Pharmacol Exp Ther. 1996 Dec;279(3):1453–1461. [PubMed] [Google Scholar]
  11. Barthel A., Kohn A. D., Luo Y., Roth R. A. A constitutively active version of the Ser/Thr kinase Akt induces production of the ob gene product, leptin, in 3T3-L1 adipocytes. Endocrinology. 1997 Aug;138(8):3559–3562. doi: 10.1210/endo.138.8.5263. [DOI] [PubMed] [Google Scholar]
  12. Bellacosa A., de Feo D., Godwin A. K., Bell D. W., Cheng J. Q., Altomare D. A., Wan M., Dubeau L., Scambia G., Masciullo V. Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int J Cancer. 1995 Aug 22;64(4):280–285. doi: 10.1002/ijc.2910640412. [DOI] [PubMed] [Google Scholar]
  13. Bliska J. B., Guan K. L., Dixon J. E., Falkow S. Tyrosine phosphate hydrolysis of host proteins by an essential Yersinia virulence determinant. Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1187–1191. doi: 10.1073/pnas.88.4.1187. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Burgering B. M., Coffer P. J. Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature. 1995 Aug 17;376(6541):599–602. doi: 10.1038/376599a0. [DOI] [PubMed] [Google Scholar]
  15. CRAIG J. W., LARNER J. INFLUENCE OF EPINEPHRINE AND INSULIN ON URIDINE DIPHOSPHATE GLUCOSE-ALPHA-GLUCAN TRANSFERASE AND PHOSPHORYLASE IN MUSCLE. Nature. 1964 Jun 6;202:971–973. doi: 10.1038/202971a0. [DOI] [PubMed] [Google Scholar]
  16. Cheng J. Q., Godwin A. K., Bellacosa A., Taguchi T., Franke T. F., Hamilton T. C., Tsichlis P. N., Testa J. R. AKT2, a putative oncogene encoding a member of a subfamily of protein-serine/threonine kinases, is amplified in human ovarian carcinomas. Proc Natl Acad Sci U S A. 1992 Oct 1;89(19):9267–9271. doi: 10.1073/pnas.89.19.9267. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Cheng J. Q., Ruggeri B., Klein W. M., Sonoda G., Altomare D. A., Watson D. K., Testa J. R. Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3636–3641. doi: 10.1073/pnas.93.8.3636. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Chung J., Kuo C. J., Crabtree G. R., Blenis J. Rapamycin-FKBP specifically blocks growth-dependent activation of and signaling by the 70 kd S6 protein kinases. Cell. 1992 Jun 26;69(7):1227–1236. doi: 10.1016/0092-8674(92)90643-q. [DOI] [PubMed] [Google Scholar]
  19. Coffer P. J., Woodgett J. R. Molecular cloning and characterisation of a novel putative protein-serine kinase related to the cAMP-dependent and protein kinase C families. Eur J Biochem. 1991 Oct 15;201(2):475–481. doi: 10.1111/j.1432-1033.1991.tb16305.x. [DOI] [PubMed] [Google Scholar]
  20. Cohen P., Holmes C. F., Tsukitani Y. Okadaic acid: a new probe for the study of cellular regulation. Trends Biochem Sci. 1990 Mar;15(3):98–102. doi: 10.1016/0968-0004(90)90192-e. [DOI] [PubMed] [Google Scholar]
  21. Cohen P. The role of calcium ions, calmodulin and troponin in the regulation of phosphorylase kinase from rabbit skeletal muscle. Eur J Biochem. 1980 Oct;111(2):563–574. doi: 10.1111/j.1432-1033.1980.tb04972.x. [DOI] [PubMed] [Google Scholar]
  22. Cohen P. The role of cyclic-AMP-dependent protein kinase in the regulation of glycogen metabolism in mammalian skeletal muscle. Curr Top Cell Regul. 1978;14:117–196. doi: 10.1016/b978-0-12-152814-0.50008-3. [DOI] [PubMed] [Google Scholar]
  23. Cohen P. The role of protein phosphorylation in neural and hormonal control of cellular activity. Nature. 1982 Apr 15;296(5858):613–620. doi: 10.1038/296613a0. [DOI] [PubMed] [Google Scholar]
  24. Cohen P. The role of protein phosphorylation in the hormonal control of enzyme activity. Eur J Biochem. 1985 Sep 16;151(3):439–448. doi: 10.1111/j.1432-1033.1985.tb09121.x. [DOI] [PubMed] [Google Scholar]
  25. Cohen P. The search for physiological substrates of MAP and SAP kinases in mammalian cells. Trends Cell Biol. 1997 Sep;7(9):353–361. doi: 10.1016/S0962-8924(97)01105-7. [DOI] [PubMed] [Google Scholar]
  26. Cross D. A., Alessi D. R., Cohen P., Andjelkovich M., Hemmings B. A. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature. 1995 Dec 21;378(6559):785–789. doi: 10.1038/378785a0. [DOI] [PubMed] [Google Scholar]
  27. Cross D. A., Watt P. W., Shaw M., van der Kaay J., Downes C. P., Holder J. C., Cohen P. Insulin activates protein kinase B, inhibits glycogen synthase kinase-3 and activates glycogen synthase by rapamycin-insensitive pathways in skeletal muscle and adipose tissue. FEBS Lett. 1997 Apr 7;406(1-2):211–215. doi: 10.1016/s0014-5793(97)00240-8. [DOI] [PubMed] [Google Scholar]
  28. Datta S. R., Dudek H., Tao X., Masters S., Fu H., Gotoh Y., Greenberg M. E. Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell. 1997 Oct 17;91(2):231–241. doi: 10.1016/s0092-8674(00)80405-5. [DOI] [PubMed] [Google Scholar]
  29. Deprez J., Vertommen D., Alessi D. R., Hue L., Rider M. H. Phosphorylation and activation of heart 6-phosphofructo-2-kinase by protein kinase B and other protein kinases of the insulin signaling cascades. J Biol Chem. 1997 Jul 11;272(28):17269–17275. doi: 10.1074/jbc.272.28.17269. [DOI] [PubMed] [Google Scholar]
  30. Dudley D. T., Pang L., Decker S. J., Bridges A. J., Saltiel A. R. A synthetic inhibitor of the mitogen-activated protein kinase cascade. Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7686–7689. doi: 10.1073/pnas.92.17.7686. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Egloff M. P., Johnson D. F., Moorhead G., Cohen P. T., Cohen P., Barford D. Structural basis for the recognition of regulatory subunits by the catalytic subunit of protein phosphatase 1. EMBO J. 1997 Apr 15;16(8):1876–1887. doi: 10.1093/emboj/16.8.1876. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Eldar-Finkelman H., Krebs E. G. Phosphorylation of insulin receptor substrate 1 by glycogen synthase kinase 3 impairs insulin action. Proc Natl Acad Sci U S A. 1997 Sep 2;94(18):9660–9664. doi: 10.1073/pnas.94.18.9660. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Embi N., Rylatt D. B., Cohen P. Glycogen synthase kinase-3 from rabbit skeletal muscle. Separation from cyclic-AMP-dependent protein kinase and phosphorylase kinase. Eur J Biochem. 1980 Jun;107(2):519–527. [PubMed] [Google Scholar]
  34. FRIEDMAN D. L., LARNER J. STUDIES ON UDPG-ALPHA-GLUCAN TRANSGLUCOSYLASE. III. INTERCONVERSION OF TWO FORMS OF MUSCLE UDPG-ALPHA-GLUCAN TRANSGLUCOSYLASE BY A PHOSPHORYLATION-DEPHOSPHORYLATION REACTION SEQUENCE. Biochemistry. 1963 Jul-Aug;2:669–675. doi: 10.1021/bi00904a009. [DOI] [PubMed] [Google Scholar]
  35. Franke T. F., Yang S. I., Chan T. O., Datta K., Kazlauskas A., Morrison D. K., Kaplan D. R., Tsichlis P. N. The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase. Cell. 1995 Jun 2;81(5):727–736. doi: 10.1016/0092-8674(95)90534-0. [DOI] [PubMed] [Google Scholar]
  36. Hubbard M. J., Cohen P. On target with a new mechanism for the regulation of protein phosphorylation. Trends Biochem Sci. 1993 May;18(5):172–177. doi: 10.1016/0968-0004(93)90109-z. [DOI] [PubMed] [Google Scholar]
  37. Hughes K., Nikolakaki E., Plyte S. E., Totty N. F., Woodgett J. R. Modulation of the glycogen synthase kinase-3 family by tyrosine phosphorylation. EMBO J. 1993 Feb;12(2):803–808. doi: 10.1002/j.1460-2075.1993.tb05715.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Hughes K., Ramakrishna S., Benjamin W. B., Woodgett J. R. Identification of multifunctional ATP-citrate lyase kinase as the alpha-isoform of glycogen synthase kinase-3. Biochem J. 1992 Nov 15;288(Pt 1):309–314. doi: 10.1042/bj2880309. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. James S. R., Downes C. P., Gigg R., Grove S. J., Holmes A. B., Alessi D. R. Specific binding of the Akt-1 protein kinase to phosphatidylinositol 3,4,5-trisphosphate without subsequent activation. Biochem J. 1996 May 1;315(Pt 3):709–713. doi: 10.1042/bj3150709. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Jefferies H. B., Reinhard C., Kozma S. C., Thomas G. Rapamycin selectively represses translation of the "polypyrimidine tract" mRNA family. Proc Natl Acad Sci U S A. 1994 May 10;91(10):4441–4445. doi: 10.1073/pnas.91.10.4441. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Jones P. F., Jakubowicz T., Pitossi F. J., Maurer F., Hemmings B. A. Molecular cloning and identification of a serine/threonine protein kinase of the second-messenger subfamily. Proc Natl Acad Sci U S A. 1991 May 15;88(10):4171–4175. doi: 10.1073/pnas.88.10.4171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Kasuga M., Karlsson F. A., Kahn C. R. Insulin stimulates the phosphorylation of the 95,000-dalton subunit of its own receptor. Science. 1982 Jan 8;215(4529):185–187. doi: 10.1126/science.7031900. [DOI] [PubMed] [Google Scholar]
  43. Kohn A. D., Summers S. A., Birnbaum M. J., Roth R. A. Expression of a constitutively active Akt Ser/Thr kinase in 3T3-L1 adipocytes stimulates glucose uptake and glucose transporter 4 translocation. J Biol Chem. 1996 Dec 6;271(49):31372–31378. doi: 10.1074/jbc.271.49.31372. [DOI] [PubMed] [Google Scholar]
  44. Lefebvre V., Méchin M. C., Louckx M. P., Rider M. H., Hue L. Signaling pathway involved in the activation of heart 6-phosphofructo-2-kinase by insulin. J Biol Chem. 1996 Sep 13;271(37):22289–22292. doi: 10.1074/jbc.271.37.22289. [DOI] [PubMed] [Google Scholar]
  45. Leung T., Chen X. Q., Manser E., Lim L. The p160 RhoA-binding kinase ROK alpha is a member of a kinase family and is involved in the reorganization of the cytoskeleton. Mol Cell Biol. 1996 Oct;16(10):5313–5327. doi: 10.1128/mcb.16.10.5313. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Liu J., Farmer J. D., Jr, Lane W. S., Friedman J., Weissman I., Schreiber S. L. Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell. 1991 Aug 23;66(4):807–815. doi: 10.1016/0092-8674(91)90124-h. [DOI] [PubMed] [Google Scholar]
  47. MacKintosh C., Beattie K. A., Klumpp S., Cohen P., Codd G. A. Cyanobacterial microcystin-LR is a potent and specific inhibitor of protein phosphatases 1 and 2A from both mammals and higher plants. FEBS Lett. 1990 May 21;264(2):187–192. doi: 10.1016/0014-5793(90)80245-e. [DOI] [PubMed] [Google Scholar]
  48. MacKintosh C., MacKintosh R. W. Inhibitors of protein kinases and phosphatases. Trends Biochem Sci. 1994 Nov;19(11):444–448. doi: 10.1016/0968-0004(94)90127-9. [DOI] [PubMed] [Google Scholar]
  49. MacKintosh R. W., Dalby K. N., Campbell D. G., Cohen P. T., Cohen P., MacKintosh C. The cyanobacterial toxin microcystin binds covalently to cysteine-273 on protein phosphatase 1. FEBS Lett. 1995 Sep 11;371(3):236–240. doi: 10.1016/0014-5793(95)00888-g. [DOI] [PubMed] [Google Scholar]
  50. Marte B. M., Downward J. PKB/Akt: connecting phosphoinositide 3-kinase to cell survival and beyond. Trends Biochem Sci. 1997 Sep;22(9):355–358. doi: 10.1016/s0968-0004(97)01097-9. [DOI] [PubMed] [Google Scholar]
  51. Myers M. G., Jr, Sun X. J., White M. F. The IRS-1 signaling system. Trends Biochem Sci. 1994 Jul;19(7):289–293. doi: 10.1016/0968-0004(94)90007-8. [DOI] [PubMed] [Google Scholar]
  52. Nakielny S., Campbell D. G., Cohen P. The molecular mechanism by which adrenalin inhibits glycogen synthesis. Eur J Biochem. 1991 Aug 1;199(3):713–722. doi: 10.1111/j.1432-1033.1991.tb16175.x. [DOI] [PubMed] [Google Scholar]
  53. Parker P. J., Caudwell F. B., Cohen P. Glycogen synthase from rabbit skeletal muscle; effect of insulin on the state of phosphorylation of the seven phosphoserine residues in vivo. Eur J Biochem. 1983 Jan 17;130(1):227–234. doi: 10.1111/j.1432-1033.1983.tb07140.x. [DOI] [PubMed] [Google Scholar]
  54. Pawson T., Gish G. D. SH2 and SH3 domains: from structure to function. Cell. 1992 Oct 30;71(3):359–362. doi: 10.1016/0092-8674(92)90504-6. [DOI] [PubMed] [Google Scholar]
  55. Poulter L., Ang S. G., Gibson B. W., Williams D. H., Holmes C. F., Caudwell F. B., Pitcher J., Cohen P. Analysis of the in vivo phosphorylation state of rabbit skeletal muscle glycogen synthase by fast-atom-bombardment mass spectrometry. Eur J Biochem. 1988 Aug 15;175(3):497–510. doi: 10.1111/j.1432-1033.1988.tb14222.x. [DOI] [PubMed] [Google Scholar]
  56. Pullen N., Thomas G. The modular phosphorylation and activation of p70s6k. FEBS Lett. 1997 Jun 23;410(1):78–82. doi: 10.1016/s0014-5793(97)00323-2. [DOI] [PubMed] [Google Scholar]
  57. Rylatt D. B., Aitken A., Bilham T., Condon G. D., Embi N., Cohen P. Glycogen synthase from rabbit skeletal muscle. Amino acid sequence at the sites phosphorylated by glycogen synthase kinase-3, and extension of the N-terminal sequence containing the site phosphorylated by phosphorylase kinase. Eur J Biochem. 1980 Jun;107(2):529–537. [PubMed] [Google Scholar]
  58. Schlender K. K., Wei S. H., Villar-Palasi C. UDP-glucose:glycogen alpha-4-glucosyltransferase I kinase activity of purified muscle protein kinase. Cyclic nucleotide specificity. Biochim Biophys Acta. 1969 Nov 4;191(2):272–278. doi: 10.1016/0005-2744(69)90246-0. [DOI] [PubMed] [Google Scholar]
  59. Soderling T. R., Hickenbottom J. P., Reimann E. M., Hunkeler F. L., Walsh D. A., Krebs E. G. Inactivation of glycogen synthetase and activation of phosphorylase kinase by muscle adenosine 3',5'-monophosphate-dependent protein kinases. J Biol Chem. 1970 Dec 10;245(23):6317–6328. [PubMed] [Google Scholar]
  60. Stewart A. A., Ingebritsen T. S., Manalan A., Klee C. B., Cohen P. Discovery of a Ca2+- and calmodulin-dependent protein phosphatase: probable identity with calcineurin (CaM-BP80). FEBS Lett. 1982 Jan 11;137(1):80–84. doi: 10.1016/0014-5793(82)80319-0. [DOI] [PubMed] [Google Scholar]
  61. Stokoe D., Stephens L. R., Copeland T., Gaffney P. R., Reese C. B., Painter G. F., Holmes A. B., McCormick F., Hawkins P. T. Dual role of phosphatidylinositol-3,4,5-trisphosphate in the activation of protein kinase B. Science. 1997 Jul 25;277(5325):567–570. doi: 10.1126/science.277.5325.567. [DOI] [PubMed] [Google Scholar]
  62. Sun X. J., Wang L. M., Zhang Y., Yenush L., Myers M. G., Jr, Glasheen E., Lane W. S., Pierce J. H., White M. F. Role of IRS-2 in insulin and cytokine signalling. Nature. 1995 Sep 14;377(6545):173–177. doi: 10.1038/377173a0. [DOI] [PubMed] [Google Scholar]
  63. Sutherland C., Cohen P. The alpha-isoform of glycogen synthase kinase-3 from rabbit skeletal muscle is inactivated by p70 S6 kinase or MAP kinase-activated protein kinase-1 in vitro. FEBS Lett. 1994 Jan 24;338(1):37–42. doi: 10.1016/0014-5793(94)80112-6. [DOI] [PubMed] [Google Scholar]
  64. Sutherland C., Leighton I. A., Cohen P. Inactivation of glycogen synthase kinase-3 beta by phosphorylation: new kinase connections in insulin and growth-factor signalling. Biochem J. 1993 Nov 15;296(Pt 1):15–19. doi: 10.1042/bj2960015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Ui M., Okada T., Hazeki K., Hazeki O. Wortmannin as a unique probe for an intracellular signalling protein, phosphoinositide 3-kinase. Trends Biochem Sci. 1995 Aug;20(8):303–307. doi: 10.1016/s0968-0004(00)89056-8. [DOI] [PubMed] [Google Scholar]
  66. Ushiro H., Cohen S. Identification of phosphotyrosine as a product of epidermal growth factor-activated protein kinase in A-431 cell membranes. J Biol Chem. 1980 Sep 25;255(18):8363–8365. [PubMed] [Google Scholar]
  67. Vanhaesebroeck B., Leevers S. J., Panayotou G., Waterfield M. D. Phosphoinositide 3-kinases: a conserved family of signal transducers. Trends Biochem Sci. 1997 Jul;22(7):267–272. doi: 10.1016/s0968-0004(97)01061-x. [DOI] [PubMed] [Google Scholar]
  68. Vlahos C. J., Matter W. F., Hui K. Y., Brown R. F. A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002). J Biol Chem. 1994 Feb 18;269(7):5241–5248. [PubMed] [Google Scholar]
  69. Walker K. S., Deak M., Paterson A., Hudson K., Cohen P., Alessi D. R. Activation of protein kinase B beta and gamma isoforms by insulin in vivo and by 3-phosphoinositide-dependent protein kinase-1 in vitro: comparison with protein kinase B alpha. Biochem J. 1998 Apr 1;331(Pt 1):299–308. doi: 10.1042/bj3310299. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Walsh D. A., Perkins J. P., Krebs E. G. An adenosine 3',5'-monophosphate-dependant protein kinase from rabbit skeletal muscle. J Biol Chem. 1968 Jul 10;243(13):3763–3765. [PubMed] [Google Scholar]
  71. Welsh G. I., Proud C. G. Glycogen synthase kinase-3 is rapidly inactivated in response to insulin and phosphorylates eukaryotic initiation factor eIF-2B. Biochem J. 1993 Sep 15;294(Pt 3):625–629. doi: 10.1042/bj2940625. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Whitman M., Downes C. P., Keeler M., Keller T., Cantley L. Type I phosphatidylinositol kinase makes a novel inositol phospholipid, phosphatidylinositol-3-phosphate. Nature. 1988 Apr 14;332(6165):644–646. doi: 10.1038/332644a0. [DOI] [PubMed] [Google Scholar]
  73. Wijkander J., Holst L. S., Rahn T., Resjö S., Castan I., Manganiello V., Belfrage P., Degerman E. Regulation of protein kinase B in rat adipocytes by insulin, vanadate, and peroxovanadate. Membrane translocation in response to peroxovanadate. J Biol Chem. 1997 Aug 22;272(34):21520–21526. doi: 10.1074/jbc.272.34.21520. [DOI] [PubMed] [Google Scholar]
  74. Woscholski R., Parker P. J. Inositol lipid 5-phosphatases--traffic signals and signal traffic. Trends Biochem Sci. 1997 Nov;22(11):427–431. doi: 10.1016/s0968-0004(97)01120-1. [DOI] [PubMed] [Google Scholar]

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