The PI3K-PDK1 connection: more than just a road to PKB.
Journal: 2000/May - Biochemical Journal
ISSN: 0264-6021
PUBMED: 10698680
Abstract:
Phosphoinositide 3-kinases (PI3Ks) generate specific inositol lipids that have been implicated in the regulation of cell growth, proliferation, survival, differentiation and cytoskeletal changes. One of the best characterized targets of PI3K lipid products is the protein kinase Akt or protein kinase B (PKB). In quiescent cells, PKB resides in the cytosol in a low-activity conformation. Upon cellular stimulation, PKB is activated through recruitment to cellular membranes by PI3K lipid products and phosphorylation by 3'-phosphoinositide-dependent kinase-1 (PDK1). Here we review the mechanism by which PKB is activated and the downstream actions of this multifunctional kinase. We also discuss the evidence that PDK1 may be involved in the activation of protein kinases other than PKB, the mechanisms by which this activity of PDK1 could be regulated and the possibility that some of the currently postulated PKB substrates targets might in fact be phosphorylated by PDK1-regulated kinases other than PKB.
Relations:
Content
Citations
(343)
References
(177)
Pathways
(1)
Chemicals
(5)
Genes
(3)
Organisms
(2)
Processes
(5)
Affiliates
(2)
Similar articles
Articles by the same authors
Discussion board
Biochem J 346(Pt 3): 561-576

The PI3K-PDK1 connection: more than just a road to PKB.

Abstract

Phosphoinositide 3-kinases (PI3Ks) generate specific inositol lipids that have been implicated in the regulation of cell growth, proliferation, survival, differentiation and cytoskeletal changes. One of the best characterized targets of PI3K lipid products is the protein kinase Akt or protein kinase B (PKB). In quiescent cells, PKB resides in the cytosol in a low-activity conformation. Upon cellular stimulation, PKB is activated through recruitment to cellular membranes by PI3K lipid products and phosphorylation by 3'-phosphoinositide-dependent kinase-1 (PDK1). Here we review the mechanism by which PKB is activated and the downstream actions of this multifunctional kinase. We also discuss the evidence that PDK1 may be involved in the activation of protein kinases other than PKB, the mechanisms by which this activity of PDK1 could be regulated and the possibility that some of the currently postulated PKB substrates targets might in fact be phosphorylated by PDK1-regulated kinases other than PKB.

Full Text

The Full Text of this article is available as a PDF (226K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Bottomley MJ, Salim K, Panayotou G. Phospholipid-binding protein domains. Biochim Biophys Acta. 1998 Dec 8;1436(1-2):165–183. [PubMed] [Google Scholar]
  • Vanhaesebroeck B, Waterfield MD. Signaling by distinct classes of phosphoinositide 3-kinases. Exp Cell Res. 1999 Nov 25;253(1):239–254. [PubMed] [Google Scholar]
  • Leevers SJ, Vanhaesebroeck B, Waterfield MD. Signalling through phosphoinositide 3-kinases: the lipids take centre stage. Curr Opin Cell Biol. 1999 Apr;11(2):219–225. [PubMed] [Google Scholar]
  • Rameh LE, Cantley LC. The role of phosphoinositide 3-kinase lipid products in cell function. J Biol Chem. 1999 Mar 26;274(13):8347–8350. [PubMed] [Google Scholar]
  • Coffer PJ, Jin J, Woodgett JR. Protein kinase B (c-Akt): a multifunctional mediator of phosphatidylinositol 3-kinase activation. Biochem J. 1998 Oct 1;335(Pt 1):1–13.[PMC free article] [PubMed] [Google Scholar]
  • Shepherd PR, Withers DJ, Siddle K. Phosphoinositide 3-kinase: the key switch mechanism in insulin signalling. Biochem J. 1998 Aug 1;333(Pt 3):471–490.[PMC free article] [PubMed] [Google Scholar]
  • Stephens LR, Jackson TR, Hawkins PT. Agonist-stimulated synthesis of phosphatidylinositol(3,4,5)-trisphosphate: a new intracellular signalling system? Biochim Biophys Acta. 1993 Oct 7;1179(1):27–75. [PubMed] [Google Scholar]
  • Wymann MP, Pirola L. Structure and function of phosphoinositide 3-kinases. Biochim Biophys Acta. 1998 Dec 8;1436(1-2):127–150. [PubMed] [Google Scholar]
  • Fruman DA, Meyers RE, Cantley LC. Phosphoinositide kinases. Annu Rev Biochem. 1998;67:481–507. [PubMed] [Google Scholar]
  • Vanhaesebroeck B, Leevers SJ, Panayotou G, Waterfield MD. Phosphoinositide 3-kinases: a conserved family of signal transducers. Trends Biochem Sci. 1997 Jul;22(7):267–272. [PubMed] [Google Scholar]
  • Woscholski R, Parker PJ. Inositol lipid 5-phosphatases--traffic signals and signal traffic. Trends Biochem Sci. 1997 Nov;22(11):427–431. [PubMed] [Google Scholar]
  • Munnik T, Irvine RF, Musgrave A. Phospholipid signalling in plants. Biochim Biophys Acta. 1998 Jan 23;1389(3):222–272. [PubMed] [Google Scholar]
  • Fruman DA, Rameh LE, Cantley LC. Phosphoinositide binding domains: embracing 3-phosphate. Cell. 1999 Jun 25;97(7):817–820. [PubMed] [Google Scholar]
  • Isakoff SJ, Cardozo T, Andreev J, Li Z, Ferguson KM, Abagyan R, Lemmon MA, Aronheim A, Skolnik EY. Identification and analysis of PH domain-containing targets of phosphatidylinositol 3-kinase using a novel in vivo assay in yeast. EMBO J. 1998 Sep 15;17(18):5374–5387.[PMC free article] [PubMed] [Google Scholar]
  • Banfić H, Tang X, Batty IH, Downes CP, Chen C, Rittenhouse SE. A novel integrin-activated pathway forms PKB/Akt-stimulatory phosphatidylinositol 3,4-bisphosphate via phosphatidylinositol 3-phosphate in platelets. J Biol Chem. 1998 Jan 2;273(1):13–16. [PubMed] [Google Scholar]
  • James SR, Downes CP, Gigg R, Grove SJ, Holmes AB, Alessi DR. 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.[PMC free article] [PubMed] [Google Scholar]
  • Stephens L, Anderson K, Stokoe D, Erdjument-Bromage H, Painter GF, Holmes AB, Gaffney PR, Reese CB, McCormick F, Tempst P, et al. Protein kinase B kinases that mediate phosphatidylinositol 3,4,5-trisphosphate-dependent activation of protein kinase B. Science. 1998 Jan 30;279(5351):710–714. [PubMed] [Google Scholar]
  • Andjelković 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 Dec 12;272(50):31515–31524. [PubMed] [Google Scholar]
  • Meier R, Alessi DR, Cron P, Andjelković M, Hemmings BA. Mitogenic activation, phosphorylation, and nuclear translocation of protein kinase Bbeta. J Biol Chem. 1997 Nov 28;272(48):30491–30497. [PubMed] [Google Scholar]
  • Welch H, Eguinoa A, Stephens LR, Hawkins PT. Protein kinase B and rac are activated in parallel within a phosphatidylinositide 3OH-kinase-controlled signaling pathway. J Biol Chem. 1998 May 1;273(18):11248–11256. [PubMed] [Google Scholar]
  • Andjelković M, Jones PF, Grossniklaus U, Cron P, Schier AF, Dick M, Bilbe G, Hemmings BA. Developmental regulation of expression and activity of multiple forms of the Drosophila RAC protein kinase. J Biol Chem. 1995 Feb 24;270(8):4066–4075. [PubMed] [Google Scholar]
  • Franke TF, Tartof KD, Tsichlis PN. The SH2-like Akt homology (AH) domain of c-akt is present in multiple copies in the genome of vertebrate and invertebrate eucaryotes. Cloning and characterization of the Drosophila melanogaster c-akt homolog Dakt1. Oncogene. 1994 Jan;9(1):141–148. [PubMed] [Google Scholar]
  • Meili R, Ellsworth C, Lee S, Reddy TB, Ma H, Firtel RA. Chemoattractant-mediated transient activation and membrane localization of Akt/PKB is required for efficient chemotaxis to cAMP in Dictyostelium. EMBO J. 1999 Apr 15;18(8):2092–2105.[PMC free article] [PubMed] [Google Scholar]
  • Paradis S, Ruvkun G. Caenorhabditis elegans Akt/PKB transduces insulin receptor-like signals from AGE-1 PI3 kinase to the DAF-16 transcription factor. Genes Dev. 1998 Aug 15;12(16):2488–2498.[PMC free article] [PubMed] [Google Scholar]
  • Chen P, Lee KS, Levin DE. A pair of putative protein kinase genes (YPK1 and YPK2) is required for cell growth in Saccharomyces cerevisiae. Mol Gen Genet. 1993 Jan;236(2-3):443–447. [PubMed] [Google Scholar]
  • Casamayor A, Torrance PD, Kobayashi T, Thorner J, Alessi DR. Functional counterparts of mammalian protein kinases PDK1 and SGK in budding yeast. Curr Biol. 1999 Feb 25;9(4):186–197. [PubMed] [Google Scholar]
  • Kobayashi T, Deak M, Morrice N, Cohen P. Characterization of the structure and regulation of two novel isoforms of serum- and glucocorticoid-induced protein kinase. Biochem J. 1999 Nov 15;344(Pt 1):189–197.[PMC free article] [PubMed] [Google Scholar]
  • Park J, Leong ML, Buse P, Maiyar AC, Firestone GL, Hemmings BA. Serum and glucocorticoid-inducible kinase (SGK) is a target of the PI 3-kinase-stimulated signaling pathway. EMBO J. 1999 Jun 1;18(11):3024–3033.[PMC free article] [PubMed] [Google Scholar]
  • 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 Apr 1;7(4):261–269. [PubMed] [Google Scholar]
  • Stokoe D, Stephens LR, Copeland T, Gaffney PR, Reese CB, Painter GF, Holmes AB, McCormick F, Hawkins PT. Dual role of phosphatidylinositol-3,4,5-trisphosphate in the activation of protein kinase B. Science. 1997 Jul 25;277(5325):567–570. [PubMed] [Google Scholar]
  • Alessi DR, Deak M, Casamayor A, Caudwell FB, Morrice N, Norman DG, Gaffney P, Reese CB, MacDougall CN, Harbison D, et al. 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. [PubMed] [Google Scholar]
  • Pullen N, Dennis PB, Andjelkovic M, Dufner A, Kozma SC, Hemmings BA, Thomas G. Phosphorylation and activation of p70s6k by PDK1. Science. 1998 Jan 30;279(5351):707–710. [PubMed] [Google Scholar]
  • Casamayor A, Morrice NA, Alessi DR. Phosphorylation of Ser-241 is essential for the activity of 3-phosphoinositide-dependent protein kinase-1: identification of five sites of phosphorylation in vivo. Biochem J. 1999 Sep 1;342(Pt 2):287–292.[PMC free article] [PubMed] [Google Scholar]
  • Anderson KE, Coadwell J, Stephens LR, Hawkins PT. Translocation of PDK-1 to the plasma membrane is important in allowing PDK-1 to activate protein kinase B. Curr Biol. 1998 Jun 4;8(12):684–691. [PubMed] [Google Scholar]
  • Currie RA, Walker KS, Gray A, Deak M, Casamayor A, Downes CP, Cohen P, Alessi DR, Lucocq J. Role of phosphatidylinositol 3,4,5-trisphosphate in regulating the activity and localization of 3-phosphoinositide-dependent protein kinase-1. Biochem J. 1999 Feb 1;337(Pt 3):575–583.[PMC free article] [PubMed] [Google Scholar]
  • Dowler S, Currie RA, Downes CP, Alessi DR. DAPP1: a dual adaptor for phosphotyrosine and 3-phosphoinositides. Biochem J. 1999 Aug 15;342(Pt 1):7–12.[PMC free article] [PubMed] [Google Scholar]
  • Paradis S, Ailion M, Toker A, Thomas JH, Ruvkun G. A PDK1 homolog is necessary and sufficient to transduce AGE-1 PI3 kinase signals that regulate diapause in Caenorhabditis elegans. Genes Dev. 1999 Jun 1;13(11):1438–1452.[PMC free article] [PubMed] [Google Scholar]
  • Niederberger C, Schweingruber ME. A Schizosaccharomyces pombe gene, ksg1, that shows structural homology to the human phosphoinositide-dependent protein kinase PDK1, is essential for growth, mating and sporulation. Mol Gen Genet. 1999 Feb;261(1):177–183. [PubMed] [Google Scholar]
  • Deak M, Casamayor A, Currie RA, Downes CP, Alessi DR. Characterisation of a plant 3-phosphoinositide-dependent protein kinase-1 homologue which contains a pleckstrin homology domain. FEBS Lett. 1999 May 28;451(3):220–226. [PubMed] [Google Scholar]
  • Inagaki M, Schmelzle T, Yamaguchi K, Irie K, Hall MN, Matsumoto K. PDK1 homologs activate the Pkc1-mitogen-activated protein kinase pathway in yeast. Mol Cell Biol. 1999 Dec;19(12):8344–8352.[PMC free article] [PubMed] [Google Scholar]
  • 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 PDGF-activated phosphatidylinositol 3-kinase. Cell. 1995 Jun 2;81(5):727–736. [PubMed] [Google Scholar]
  • Franke TF, Kaplan DR, Cantley LC, Toker A. Direct regulation of the Akt proto-oncogene product by phosphatidylinositol-3,4-bisphosphate. Science. 1997 Jan 31;275(5300):665–668. [PubMed] [Google Scholar]
  • 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 Dec 2;15(23):6541–6551.[PMC free article] [PubMed] [Google Scholar]
  • Walker KS, Deak M, Paterson A, Hudson K, Cohen P, Alessi DR. 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.[PMC free article] [PubMed] [Google Scholar]
  • Delcommenne M, Tan C, Gray V, Rue L, Woodgett J, Dedhar S. Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase. Proc Natl Acad Sci U S A. 1998 Sep 15;95(19):11211–11216.[PMC free article] [PubMed] [Google Scholar]
  • Lynch DK, Ellis CA, Edwards PA, Hiles ID. Integrin-linked kinase regulates phosphorylation of serine 473 of protein kinase B by an indirect mechanism. Oncogene. 1999 Dec 23;18(56):8024–8032. [PubMed] [Google Scholar]
  • Dedhar S, Williams B, Hannigan G. Integrin-linked kinase (ILK): a regulator of integrin and growth-factor signalling. Trends Cell Biol. 1999 Aug;9(8):319–323. [PubMed] [Google Scholar]
  • Balendran A, Casamayor A, Deak M, Paterson A, Gaffney P, Currie R, Downes CP, Alessi DR. PDK1 acquires PDK2 activity in the presence of a synthetic peptide derived from the carboxyl terminus of PRK2. Curr Biol. 1999 Apr 22;9(8):393–404. [PubMed] [Google Scholar]
  • Le Good JA, Ziegler WH, Parekh DB, Alessi DR, Cohen P, Parker PJ. Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1. Science. 1998 Sep 25;281(5385):2042–2045. [PubMed] [Google Scholar]
  • Romanelli A, Martin KA, Toker A, Blenis J. p70 S6 kinase is regulated by protein kinase Czeta and participates in a phosphoinositide 3-kinase-regulated signalling complex. Mol Cell Biol. 1999 Apr;19(4):2921–2928.[PMC free article] [PubMed] [Google Scholar]
  • Balendran A, Currie R, Armstrong CG, Avruch J, Alessi DR. Evidence that 3-phosphoinositide-dependent protein kinase-1 mediates phosphorylation of p70 S6 kinase in vivo at Thr-412 as well as Thr-252. J Biol Chem. 1999 Dec 24;274(52):37400–37406. [PubMed] [Google Scholar]
  • Kohn AD, Takeuchi F, Roth RA. Akt, a pleckstrin homology domain containing kinase, is activated primarily by phosphorylation. J Biol Chem. 1996 Sep 6;271(36):21920–21926. [PubMed] [Google Scholar]
  • Andjelković M, Maira SM, Cron P, Parker PJ, Hemmings BA. Domain swapping used to investigate the mechanism of protein kinase B regulation by 3-phosphoinositide-dependent protein kinase 1 and Ser473 kinase. Mol Cell Biol. 1999 Jul;19(7):5061–5072.[PMC free article] [PubMed] [Google Scholar]
  • Moule SK, Welsh GI, Edgell NJ, Foulstone EJ, Proud CG, Denton RM. Regulation of protein kinase B and glycogen synthase kinase-3 by insulin and beta-adrenergic agonists in rat epididymal fat cells. Activation of protein kinase B by wortmannin-sensitive and -insensitive mechanisms. J Biol Chem. 1997 Mar 21;272(12):7713–7719. [PubMed] [Google Scholar]
  • Konishi H, Matsuzaki H, Tanaka M, Ono Y, Tokunaga C, Kuroda S, Kikkawa U. Activation of RAC-protein kinase by heat shock and hyperosmolarity stress through a pathway independent of phosphatidylinositol 3-kinase. Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7639–7643.[PMC free article] [PubMed] [Google Scholar]
  • Sable CL, Filippa N, Hemmings B, Van Obberghen E. cAMP stimulates protein kinase B in a Wortmannin-insensitive manner. FEBS Lett. 1997 Jun 9;409(2):253–257. [PubMed] [Google Scholar]
  • Yano S, Tokumitsu H, Soderling TR. Calcium promotes cell survival through CaM-K kinase activation of the protein-kinase-B pathway. Nature. 1998 Dec 10;396(6711):584–587. [PubMed] [Google Scholar]
  • Filippa N, Sable CL, Filloux C, Hemmings B, Van Obberghen E. Mechanism of protein kinase B activation by cyclic AMP-dependent protein kinase. Mol Cell Biol. 1999 Jul;19(7):4989–5000.[PMC free article] [PubMed] [Google Scholar]
  • Shaw M, Cohen P, Alessi DR. The activation of protein kinase B by H2O2 or heat shock is mediated by phosphoinositide 3-kinase and not by mitogen-activated protein kinase-activated protein kinase-2. Biochem J. 1998 Nov 15;336(Pt 1):241–246.[PMC free article] [PubMed] [Google Scholar]
  • Alessi DR, Caudwell FB, Andjelkovic M, Hemmings BA, 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. [PubMed] [Google Scholar]
  • Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA. Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature. 1995 Dec 21;378(6559):785–789. [PubMed] [Google Scholar]
  • Bertrand L, Alessi DR, Deprez J, Deak M, Viaene E, Rider MH, Hue L. Heart 6-phosphofructo-2-kinase activation by insulin results from Ser-466 and Ser-483 phosphorylation and requires 3-phosphoinositide-dependent kinase-1, but not protein kinase B. J Biol Chem. 1999 Oct 22;274(43):30927–30933. [PubMed] [Google Scholar]
  • Wang Q, Somwar R, Bilan PJ, Liu Z, Jin J, Woodgett JR, Klip A. Protein kinase B/Akt participates in GLUT4 translocation by insulin in L6 myoblasts. Mol Cell Biol. 1999 Jun;19(6):4008–4018.[PMC free article] [PubMed] [Google Scholar]
  • van Weeren PC, de Bruyn KM, de Vries-Smits AM, van Lint J, Burgering BM. Essential role for protein kinase B (PKB) in insulin-induced glycogen synthase kinase 3 inactivation. Characterization of dominant-negative mutant of PKB. J Biol Chem. 1998 May 22;273(21):13150–13156. [PubMed] [Google Scholar]
  • Franke TF, Kaplan DR, Cantley LC. PI3K: downstream AKTion blocks apoptosis. Cell. 1997 Feb 21;88(4):435–437. [PubMed] [Google Scholar]
  • Downward J. Mechanisms and consequences of activation of protein kinase B/Akt. Curr Opin Cell Biol. 1998 Apr;10(2):262–267. [PubMed] [Google Scholar]
  • Sabbatini P, McCormick F. Phosphoinositide 3-OH kinase (PI3K) and PKB/Akt delay the onset of p53-mediated, transcriptionally dependent apoptosis. J Biol Chem. 1999 Aug 20;274(34):24263–24269. [PubMed] [Google Scholar]
  • Bellacosa A, de Feo D, Godwin AK, Bell DW, Cheng JQ, Altomare DA, Wan M, Dubeau L, Scambia G, Masciullo V, et al. Molecular alterations of the AKT2 oncogene in ovarian and breast carcinomas. Int J Cancer. 1995 Aug 22;64(4):280–285. [PubMed] [Google Scholar]
  • Nakatani K, Thompson DA, Barthel A, Sakaue H, Liu W, Weigel RJ, Roth RA. Up-regulation of Akt3 in estrogen receptor-deficient breast cancers and androgen-independent prostate cancer lines. J Biol Chem. 1999 Jul 30;274(31):21528–21532. [PubMed] [Google Scholar]
  • Cheng JQ, Ruggeri B, Klein WM, Sonoda G, Altomare DA, Watson DK, Testa JR. 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.[PMC free article] [PubMed] [Google Scholar]
  • Cheng JQ, Godwin AK, Bellacosa A, Taguchi T, Franke TF, Hamilton TC, Tsichlis PN, Testa JR. 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.[PMC free article] [PubMed] [Google Scholar]
  • Aoki M, Batista O, Bellacosa A, Tsichlis P, Vogt PK. The akt kinase: molecular determinants of oncogenicity. Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14950–14955.[PMC free article] [PubMed] [Google Scholar]
  • Li DM, Sun H. PTEN/MMAC1/TEP1 suppresses the tumorigenicity and induces G1 cell cycle arrest in human glioblastoma cells. Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15406–15411.[PMC free article] [PubMed] [Google Scholar]
  • Furnari FB, Huang HJ, Cavenee WK. The phosphoinositol phosphatase activity of PTEN mediates a serum-sensitive G1 growth arrest in glioma cells. Cancer Res. 1998 Nov 15;58(22):5002–5008. [PubMed] [Google Scholar]
  • Wu X, Senechal K, Neshat MS, Whang YE, Sawyers CL. The PTEN/MMAC1 tumor suppressor phosphatase functions as a negative regulator of the phosphoinositide 3-kinase/Akt pathway. Proc Natl Acad Sci U S A. 1998 Dec 22;95(26):15587–15591.[PMC free article] [PubMed] [Google Scholar]
  • Stambolic V, Suzuki A, de la Pompa JL, Brothers GM, Mirtsos C, Sasaki T, Ruland J, Penninger JM, Siderovski DP, Mak TW. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell. 1998 Oct 2;95(1):29–39. [PubMed] [Google Scholar]
  • Suzuki A, de la Pompa JL, Stambolic V, Elia AJ, Sasaki T, del Barco Barrantes I, Ho A, Wakeham A, Itie A, Khoo W, et al. High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Curr Biol. 1998 Oct 22;8(21):1169–1178. [PubMed] [Google Scholar]
  • Haas-Kogan D, Shalev N, Wong M, Mills G, Yount G, Stokoe D. Protein kinase B (PKB/Akt) activity is elevated in glioblastoma cells due to mutation of the tumor suppressor PTEN/MMAC. Curr Biol. 1998 Oct 22;8(21):1195–1198. [PubMed] [Google Scholar]
  • Myers MP, Pass I, Batty IH, Van der Kaay J, Stolarov JP, Hemmings BA, Wigler MH, Downes CP, Tonks NK. The lipid phosphatase activity of PTEN is critical for its tumor supressor function. Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13513–13518.[PMC free article] [PubMed] [Google Scholar]
  • Li HL, Davis WW, Whiteman EL, Birnbaum MJ, Puré E. The tyrosine kinases Syk and Lyn exert opposing effects on the activation of protein kinase Akt/PKB in B lymphocytes. Proc Natl Acad Sci U S A. 1999 Jun 8;96(12):6890–6895.[PMC free article] [PubMed] [Google Scholar]
  • Craxton A, Jiang A, Kurosaki T, Clark EA. Syk and Bruton's tyrosine kinase are required for B cell antigen receptor-mediated activation of the kinase Akt. J Biol Chem. 1999 Oct 22;274(43):30644–30650. [PubMed] [Google Scholar]
  • Craddock BL, Orchiston EA, Hinton HJ, Welham MJ. Dissociation of apoptosis from proliferation, protein kinase B activation, and BAD phosphorylation in interleukin-3-mediated phosphoinositide 3-kinase signaling. J Biol Chem. 1999 Apr 9;274(15):10633–10640. [PubMed] [Google Scholar]
  • Brennan P, Babbage JW, Burgering BM, Groner B, Reif K, Cantrell DA. Phosphatidylinositol 3-kinase couples the interleukin-2 receptor to the cell cycle regulator E2F. Immunity. 1997 Nov;7(5):679–689. [PubMed] [Google Scholar]
  • Brennan P, Babbage JW, Thomas G, Cantrell D. p70(s6k) integrates phosphatidylinositol 3-kinase and rapamycin-regulated signals for E2F regulation in T lymphocytes. Mol Cell Biol. 1999 Jul;19(7):4729–4738.[PMC free article] [PubMed] [Google Scholar]
  • Diehl JA, Cheng M, Roussel MF, Sherr CJ. Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev. 1998 Nov 15;12(22):3499–3511.[PMC free article] [PubMed] [Google Scholar]
  • Muise-Helmericks RC, Grimes HL, Bellacosa A, Malstrom SE, Tsichlis PN, Rosen N. Cyclin D expression is controlled post-transcriptionally via a phosphatidylinositol 3-kinase/Akt-dependent pathway. J Biol Chem. 1998 Nov 6;273(45):29864–29872. [PubMed] [Google Scholar]
  • Downward J. How BAD phosphorylation is good for survival. Nat Cell Biol. 1999 Jun;1(2):E33–E35. [PubMed] [Google Scholar]
  • Scheid MP, Duronio V. Dissociation of cytokine-induced phosphorylation of Bad and activation of PKB/akt: involvement of MEK upstream of Bad phosphorylation. Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7439–7444.[PMC free article] [PubMed] [Google Scholar]
  • Hinton HJ, Welham MJ. Cytokine-induced protein kinase B activation and Bad phosphorylation do not correlate with cell survival of hemopoietic cells. J Immunol. 1999 Jun 15;162(12):7002–7009. [PubMed] [Google Scholar]
  • Pastorino JG, Tafani M, Farber JL. Tumor necrosis factor induces phosphorylation and translocation of BAD through a phosphatidylinositide-3-OH kinase-dependent pathway. J Biol Chem. 1999 Jul 2;274(27):19411–19416. [PubMed] [Google Scholar]
  • Kennedy SG, Kandel ES, Cross TK, Hay N. Akt/Protein kinase B inhibits cell death by preventing the release of cytochrome c from mitochondria. Mol Cell Biol. 1999 Aug;19(8):5800–5810.[PMC free article] [PubMed] [Google Scholar]
  • Harada H, Becknell B, Wilm M, Mann M, Huang LJ, Taylor SS, Scott JD, Korsmeyer SJ. Phosphorylation and inactivation of BAD by mitochondria-anchored protein kinase A. Mol Cell. 1999 Apr;3(4):413–422. [PubMed] [Google Scholar]
  • Scheid MP, Schubert KM, Duronio V. Regulation of bad phosphorylation and association with Bcl-x(L) by the MAPK/Erk kinase. J Biol Chem. 1999 Oct 22;274(43):31108–31113. [PubMed] [Google Scholar]
  • Bonni A, Brunet A, West AE, Datta SR, Takasu MA, Greenberg ME. Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science. 1999 Nov 12;286(5443):1358–1362. [PubMed] [Google Scholar]
  • Kennedy SG, Wagner AJ, Conzen SD, Jordán J, Bellacosa A, Tsichlis PN, Hay N. The PI 3-kinase/Akt signaling pathway delivers an anti-apoptotic signal. Genes Dev. 1997 Mar 15;11(6):701–713. [PubMed] [Google Scholar]
  • Skorski T, Bellacosa A, Nieborowska-Skorska M, Majewski M, Martinez R, Choi JK, Trotta R, Wlodarski P, Perrotti D, Chan TO, et al. Transformation of hematopoietic cells by BCR/ABL requires activation of a PI-3k/Akt-dependent pathway. EMBO J. 1997 Oct 15;16(20):6151–6161.[PMC free article] [PubMed] [Google Scholar]
  • Alnemri ES. Hidden powers of the mitochondria. Nat Cell Biol. 1999 Jun;1(2):E40–E42. [PubMed] [Google Scholar]
  • Wolf BB, Green DR. Suicidal tendencies: apoptotic cell death by caspase family proteinases. J Biol Chem. 1999 Jul 16;274(29):20049–20052. [PubMed] [Google Scholar]
  • Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, Frisch S, Reed JC. Regulation of cell death protease caspase-9 by phosphorylation. Science. 1998 Nov 13;282(5392):1318–1321. [PubMed] [Google Scholar]
  • Fujita E, Jinbo A, Matuzaki H, Konishi H, Kikkawa U, Momoi T. Akt phosphorylation site found in human caspase-9 is absent in mouse caspase-9. Biochem Biophys Res Commun. 1999 Oct 22;264(2):550–555. [PubMed] [Google Scholar]
  • Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell. 1999 Mar 19;96(6):857–868. [PubMed] [Google Scholar]
  • Kops GJ, de Ruiter ND, De Vries-Smits AM, Powell DR, Bos JL, Burgering BM. Direct control of the Forkhead transcription factor AFX by protein kinase B. Nature. 1999 Apr 15;398(6728):630–634. [PubMed] [Google Scholar]
  • Rena G, Guo S, Cichy SC, Unterman TG, Cohen P. Phosphorylation of the transcription factor forkhead family member FKHR by protein kinase B. J Biol Chem. 1999 Jun 11;274(24):17179–17183. [PubMed] [Google Scholar]
  • Biggs WH, 3rd, Meisenhelder J, Hunter T, Cavenee WK, Arden KC. Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1. Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7421–7426.[PMC free article] [PubMed] [Google Scholar]
  • Guo S, Rena G, Cichy S, He X, Cohen P, Unterman T. Phosphorylation of serine 256 by protein kinase B disrupts transactivation by FKHR and mediates effects of insulin on insulin-like growth factor-binding protein-1 promoter activity through a conserved insulin response sequence. J Biol Chem. 1999 Jun 11;274(24):17184–17192. [PubMed] [Google Scholar]
  • Ogg S, Paradis S, Gottlieb S, Patterson GI, Lee L, Tissenbaum HA, Ruvkun G. The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature. 1997 Oct 30;389(6654):994–999. [PubMed] [Google Scholar]
  • Khwaja A. Akt is more than just a Bad kinase. Nature. 1999 Sep 2;401(6748):33–34. [PubMed] [Google Scholar]
  • Romashkova JA, Makarov SS. NF-kappaB is a target of AKT in anti-apoptotic PDGF signalling. Nature. 1999 Sep 2;401(6748):86–90. [PubMed] [Google Scholar]
  • Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB. NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature. 1999 Sep 2;401(6748):82–85. [PubMed] [Google Scholar]
  • Kane LP, Shapiro VS, Stokoe D, Weiss A. Induction of NF-kappaB by the Akt/PKB kinase. Curr Biol. 1999 Jun 3;9(11):601–604. [PubMed] [Google Scholar]
  • Wang CY, Guttridge DC, Mayo MW, Baldwin AS., Jr NF-kappaB induces expression of the Bcl-2 homologue A1/Bfl-1 to preferentially suppress chemotherapy-induced apoptosis. Mol Cell Biol. 1999 Sep;19(9):5923–5929.[PMC free article] [PubMed] [Google Scholar]
  • Wang CY, Mayo MW, Korneluk RG, Goeddel DV, Baldwin AS., Jr NF-kappaB antiapoptosis: induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science. 1998 Sep 11;281(5383):1680–1683. [PubMed] [Google Scholar]
  • Kohn AD, Summers SA, Birnbaum MJ, Roth RA. 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. [PubMed] [Google Scholar]
  • Kohn AD, Barthel A, Kovacina KS, Boge A, Wallach B, Summers SA, Birnbaum MJ, Scott PH, Lawrence JC, Jr, Roth RA. Construction and characterization of a conditionally active version of the serine/threonine kinase Akt. J Biol Chem. 1998 May 8;273(19):11937–11943. [PubMed] [Google Scholar]
  • Liao J, Barthel A, Nakatani K, Roth RA. Activation of protein kinase B/Akt is sufficient to repress the glucocorticoid and cAMP induction of phosphoenolpyruvate carboxykinase gene. J Biol Chem. 1998 Oct 16;273(42):27320–27324. [PubMed] [Google Scholar]
  • Hajduch E, Alessi DR, Hemmings BA, Hundal HS. Constitutive activation of protein kinase B alpha by membrane targeting promotes glucose and system A amino acid transport, protein synthesis, and inactivation of glycogen synthase kinase 3 in L6 muscle cells. Diabetes. 1998 Jul;47(7):1006–1013. [PubMed] [Google Scholar]
  • Takata M, Ogawa W, Kitamura T, Hino Y, Kuroda S, Kotani K, Klip A, Gingras AC, Sonenberg N, Kasuga M. Requirement for Akt (protein kinase B) in insulin-induced activation of glycogen synthase and phosphorylation of 4E-BP1 (PHAS-1). J Biol Chem. 1999 Jul 16;274(29):20611–20618. [PubMed] [Google Scholar]
  • Barthel A, Okino ST, Liao J, Nakatani K, Li J, Whitlock JP, Jr, Roth RA. Regulation of GLUT1 gene transcription by the serine/threonine kinase Akt1. J Biol Chem. 1999 Jul 16;274(29):20281–20286. [PubMed] [Google Scholar]
  • Barthel A, Kohn AD, Luo Y, Roth RA. 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. [PubMed] [Google Scholar]
  • Wang D, Sul HS. Insulin stimulation of the fatty acid synthase promoter is mediated by the phosphatidylinositol 3-kinase pathway. Involvement of protein kinase B/Akt. J Biol Chem. 1998 Sep 25;273(39):25420–25426. [PubMed] [Google Scholar]
  • Kitamura T, Ogawa W, Sakaue H, Hino Y, Kuroda S, Takata M, Matsumoto M, Maeda T, Konishi H, Kikkawa U, et al. Requirement for activation of the serine-threonine kinase Akt (protein kinase B) in insulin stimulation of protein synthesis but not of glucose transport. Mol Cell Biol. 1998 Jul;18(7):3708–3717.[PMC free article] [PubMed] [Google Scholar]
  • Kotani K, Ogawa W, Hino Y, Kitamura T, Ueno H, Sano W, Sutherland C, Granner DK, Kasuga M. Dominant negative forms of Akt (protein kinase B) and atypical protein kinase Clambda do not prevent insulin inhibition of phosphoenolpyruvate carboxykinase gene transcription. J Biol Chem. 1999 Jul 23;274(30):21305–21312. [PubMed] [Google Scholar]
  • Krook A, Roth RA, Jiang XJ, Zierath JR, Wallberg-Henriksson H. Insulin-stimulated Akt kinase activity is reduced in skeletal muscle from NIDDM subjects. Diabetes. 1998 Aug;47(8):1281–1286. [PubMed] [Google Scholar]
  • Rondinone CM, Carvalho E, Wesslau C, Smith UP. Impaired glucose transport and protein kinase B activation by insulin, but not okadaic acid, in adipocytes from subjects with Type II diabetes mellitus. Diabetologia. 1999 Jul;42(7):819–825. [PubMed] [Google Scholar]
  • Scott PH, Brunn GJ, Kohn AD, Roth RA, Lawrence JC., Jr Evidence of insulin-stimulated phosphorylation and activation of the mammalian target of rapamycin mediated by a protein kinase B signaling pathway. Proc Natl Acad Sci U S A. 1998 Jun 23;95(13):7772–7777.[PMC free article] [PubMed] [Google Scholar]
  • Navé BT, Ouwens M, Withers DJ, Alessi DR, Shepherd PR. Mammalian target of rapamycin is a direct target for protein kinase B: identification of a convergence point for opposing effects of insulin and amino-acid deficiency on protein translation. Biochem J. 1999 Dec 1;344(Pt 2):427–431.[PMC free article] [PubMed] [Google Scholar]
  • Nakae J, Park BC, Accili D. Insulin stimulates phosphorylation of the forkhead transcription factor FKHR on serine 253 through a Wortmannin-sensitive pathway. J Biol Chem. 1999 Jun 4;274(23):15982–15985. [PubMed] [Google Scholar]
  • Li J, DeFea K, Roth RA. Modulation of insulin receptor substrate-1 tyrosine phosphorylation by an Akt/phosphatidylinositol 3-kinase pathway. J Biol Chem. 1999 Apr 2;274(14):9351–9356. [PubMed] [Google Scholar]
  • Paz K, Liu YF, Shorer H, Hemi R, LeRoith D, Quan M, Kanety H, Seger R, Zick Y. Phosphorylation of insulin receptor substrate-1 (IRS-1) by protein kinase B positively regulates IRS-1 function. J Biol Chem. 1999 Oct 1;274(40):28816–28822. [PubMed] [Google Scholar]
  • Alessi DR, Downes CP. The role of PI 3-kinase in insulin action. Biochim Biophys Acta. 1998 Dec 8;1436(1-2):151–164. [PubMed] [Google Scholar]
  • Leevers SJ, Weinkove D, MacDougall LK, Hafen E, Waterfield MD. The Drosophila phosphoinositide 3-kinase Dp110 promotes cell growth. EMBO J. 1996 Dec 2;15(23):6584–6594.[PMC free article] [PubMed] [Google Scholar]
  • Weinkove D, Neufeld TP, Twardzik T, Waterfield MD, Leevers SJ. Regulation of imaginal disc cell size, cell number and organ size by Drosophila class I(A) phosphoinositide 3-kinase and its adaptor. Curr Biol. 1999 Sep 23;9(18):1019–1029. [PubMed] [Google Scholar]
  • Böhni R, Riesgo-Escovar J, Oldham S, Brogiolo W, Stocker H, Andruss BF, Beckingham K, Hafen E. Autonomous control of cell and organ size by CHICO, a Drosophila homolog of vertebrate IRS1-4. Cell. 1999 Jun 25;97(7):865–875. [PubMed] [Google Scholar]
  • Chen C, Jack J, Garofalo RS. The Drosophila insulin receptor is required for normal growth. Endocrinology. 1996 Mar;137(3):846–856. [PubMed] [Google Scholar]
  • Montagne J, Stewart MJ, Stocker H, Hafen E, Kozma SC, Thomas G. Drosophila S6 kinase: a regulator of cell size. Science. 1999 Sep 24;285(5436):2126–2129. [PubMed] [Google Scholar]
  • Leevers SJ. Perspectives: cell biology. All creatures great and small. Science. 1999 Sep 24;285(5436):2082–2083. [PubMed] [Google Scholar]
  • Downward J. Ras signalling and apoptosis. Curr Opin Genet Dev. 1998 Feb;8(1):49–54. [PubMed] [Google Scholar]
  • Zimmermann S, Moelling K. Phosphorylation and regulation of Raf by Akt (protein kinase B). Science. 1999 Nov 26;286(5445):1741–1744. [PubMed] [Google Scholar]
  • Rommel C, Clarke BA, Zimmermann S, Nuñez L, Rossman R, Reid K, Moelling K, Yancopoulos GD, Glass DJ. Differentiation stage-specific inhibition of the Raf-MEK-ERK pathway by Akt. Science. 1999 Nov 26;286(5445):1738–1741. [PubMed] [Google Scholar]
  • 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 Oct 1;303(Pt 1):21–26.[PMC free article] [PubMed] [Google Scholar]
  • Wennström S, Downward J. Role of phosphoinositide 3-kinase in activation of ras and mitogen-activated protein kinase by epidermal growth factor. Mol Cell Biol. 1999 Jun;19(6):4279–4288.[PMC free article] [PubMed] [Google Scholar]
  • Duckworth BC, Cantley LC. Conditional inhibition of the mitogen-activated protein kinase cascade by wortmannin. Dependence on signal strength. J Biol Chem. 1997 Oct 31;272(44):27665–27670. [PubMed] [Google Scholar]
  • Fulton D, Gratton JP, McCabe TJ, Fontana J, Fujio Y, Walsh K, Franke TF, Papapetropoulos A, Sessa WC. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature. 1999 Jun 10;399(6736):597–601.[PMC free article] [PubMed] [Google Scholar]
  • Dimmeler S, Fleming I, Fisslthaler B, Hermann C, Busse R, Zeiher AM. Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation. Nature. 1999 Jun 10;399(6736):601–605. [PubMed] [Google Scholar]
  • Snyder SH, Jaffrey SR. Vessels vivified by Akt acting on NO synthase. Nat Cell Biol. 1999 Aug;1(4):E95–E96. [PubMed] [Google Scholar]
  • Michell BJ, Griffiths JE, Mitchelhill KI, Rodriguez-Crespo I, Tiganis T, Bozinovski S, de Montellano PR, Kemp BE, Pearson RB. The Akt kinase signals directly to endothelial nitric oxide synthase. Curr Biol. 9(15):845–848. [PubMed] [Google Scholar]
  • Gallis B, Corthals GL, Goodlett DR, Ueba H, Kim F, Presnell SR, Figeys D, Harrison DG, Berk BC, Aebersold R, et al. Identification of flow-dependent endothelial nitric-oxide synthase phosphorylation sites by mass spectrometry and regulation of phosphorylation and nitric oxide production by the phosphatidylinositol 3-kinase inhibitor LY294002. J Biol Chem. 1999 Oct 15;274(42):30101–30108. [PubMed] [Google Scholar]
  • Bertwistle D, Ashworth A. Functions of the BRCA1 and BRCA2 genes. Curr Opin Genet Dev. 1998 Feb;8(1):14–20. [PubMed] [Google Scholar]
  • Altiok S, Batt D, Altiok N, Papautsky A, Downward J, Roberts TM, Avraham H. Heregulin induces phosphorylation of BRCA1 through phosphatidylinositol 3-Kinase/AKT in breast cancer cells. J Biol Chem. 1999 Nov 5;274(45):32274–32278. [PubMed] [Google Scholar]
  • Mellor H, Parker PJ. The extended protein kinase C superfamily. Biochem J. 1998 Jun 1;332(Pt 2):281–292.[PMC free article] [PubMed] [Google Scholar]
  • Knighton DR, Zheng JH, Ten Eyck LF, Ashford VA, Xuong NH, Taylor SS, Sowadski JM. Crystal structure of the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase. Science. 1991 Jul 26;253(5018):407–414. [PubMed] [Google Scholar]
  • Belham C, Wu S, Avruch J. Intracellular signalling: PDK1--a kinase at the hub of things. Curr Biol. 1999 Feb 11;9(3):R93–R96. [PubMed] [Google Scholar]
  • Peterson RT, Schreiber SL. Kinase phosphorylation: Keeping it all in the family. Curr Biol. 1999 Jul 15;9(14):R521–R524. [PubMed] [Google Scholar]
  • Chou MM, Hou W, Johnson J, Graham LK, Lee MH, Chen CS, Newton AC, Schaffhausen BS, Toker A. Regulation of protein kinase C zeta by PI 3-kinase and PDK-1. Curr Biol. 1998 Sep 24;8(19):1069–1077. [PubMed] [Google Scholar]
  • Dutil EM, Toker A, Newton AC. Regulation of conventional protein kinase C isozymes by phosphoinositide-dependent kinase 1 (PDK-1). Curr Biol. 1998 Dec 17;8(25):1366–1375. [PubMed] [Google Scholar]
  • 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 Jan 15;8(2):69–81. [PubMed] [Google Scholar]
  • Kobayashi T, Cohen P. Activation of serum- and glucocorticoid-regulated protein kinase by agonists that activate phosphatidylinositide 3-kinase is mediated by 3-phosphoinositide-dependent protein kinase-1 (PDK1) and PDK2. Biochem J. 1999 Apr 15;339(Pt 2):319–328.[PMC free article] [PubMed] [Google Scholar]
  • Cheng X, Ma Y, Moore M, Hemmings BA, Taylor SS. Phosphorylation and activation of cAMP-dependent protein kinase by phosphoinositide-dependent protein kinase. Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):9849–9854.[PMC free article] [PubMed] [Google Scholar]
  • Edwards AS, Faux MC, Scott JD, Newton AC. Carboxyl-terminal phosphorylation regulates the function and subcellular localization of protein kinase C betaII. J Biol Chem. 1999 Mar 5;274(10):6461–6468. [PubMed] [Google Scholar]
  • Ziegler WH, Parekh DB, Le Good JA, Whelan RD, Kelly JJ, Frech M, Hemmings BA, Parker PJ. Rapamycin-sensitive phosphorylation of PKC on a carboxy-terminal site by an atypical PKC complex. Curr Biol. 1999 May 20;9(10):522–529. [PubMed] [Google Scholar]
  • Weng QP, Kozlowski M, Belham C, Zhang A, Comb MJ, Avruch J. Regulation of the p70 S6 kinase by phosphorylation in vivo. Analysis using site-specific anti-phosphopeptide antibodies. J Biol Chem. 1998 Jun 26;273(26):16621–16629. [PubMed] [Google Scholar]
  • Burnett PE, Barrow RK, Cohen NA, Snyder SH, Sabatini DM. RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1. Proc Natl Acad Sci U S A. 1998 Feb 17;95(4):1432–1437.[PMC free article] [PubMed] [Google Scholar]
  • Isotani S, Hara K, Tokunaga C, Inoue H, Avruch J, Yonezawa K. Immunopurified mammalian target of rapamycin phosphorylates and activates p70 S6 kinase alpha in vitro. J Biol Chem. 1999 Nov 26;274(48):34493–34498. [PubMed] [Google Scholar]
  • Hara K, Yonezawa K, Weng QP, Kozlowski MT, Belham C, Avruch J. Amino acid sufficiency and mTOR regulate p70 S6 kinase and eIF-4E BP1 through a common effector mechanism. J Biol Chem. 1998 Jun 5;273(23):14484–14494. [PubMed] [Google Scholar]
  • Jiang Y, Broach JR. Tor proteins and protein phosphatase 2A reciprocally regulate Tap42 in controlling cell growth in yeast. EMBO J. 1999 May 17;18(10):2782–2792.[PMC free article] [PubMed] [Google Scholar]
  • Murata K, Wu J, Brautigan DL. B cell receptor-associated protein alpha4 displays rapamycin-sensitive binding directly to the catalytic subunit of protein phosphatase 2A. Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10624–10629.[PMC free article] [PubMed] [Google Scholar]
  • Di Como CJ, Arndt KT. Nutrients, via the Tor proteins, stimulate the association of Tap42 with type 2A phosphatases. Genes Dev. 1996 Aug 1;10(15):1904–1916. [PubMed] [Google Scholar]
  • Akimoto K, Nakaya M, Yamanaka T, Tanaka J, Matsuda S, Weng QP, Avruch J, Ohno S. Atypical protein kinase Clambda binds and regulates p70 S6 kinase. Biochem J. 1998 Oct 15;335(Pt 2):417–424.[PMC free article] [PubMed] [Google Scholar]
  • Doornbos RP, Theelen M, van der Hoeven PC, van Blitterswijk WJ, Verkleij AJ, van Bergen en Henegouwen PM. Protein kinase Czeta is a negative regulator of protein kinase B activity. J Biol Chem. 1999 Mar 26;274(13):8589–8596. [PubMed] [Google Scholar]
  • Konishi H, Kuroda S, Tanaka M, Matsuzaki H, Ono Y, Kameyama K, Haga T, Kikkawa U. Molecular cloning and characterization of a new member of the RAC protein kinase family: association of the pleckstrin homology domain of three types of RAC protein kinase with protein kinase C subspecies and beta gamma subunits of G proteins. Biochem Biophys Res Commun. 1995 Nov 13;216(2):526–534. [PubMed] [Google Scholar]
  • Richards SA, Fu J, Romanelli A, Shimamura A, Blenis J. Ribosomal S6 kinase 1 (RSK1) activation requires signals dependent on and independent of the MAP kinase ERK. Curr Biol. 9(15):810–820. [PubMed] [Google Scholar]
  • Jensen CJ, Buch MB, Krag TO, Hemmings BA, Gammeltoft S, Frödin M. 90-kDa ribosomal S6 kinase is phosphorylated and activated by 3-phosphoinositide-dependent protein kinase-1. J Biol Chem. 1999 Sep 17;274(38):27168–27176. [PubMed] [Google Scholar]
  • Colledge M, Scott JD. AKAPs: from structure to function. Trends Cell Biol. 1999 Jun;9(6):216–221. [PubMed] [Google Scholar]
  • Frödin M, Gammeltoft S. Role and regulation of 90 kDa ribosomal S6 kinase (RSK) in signal transduction. Mol Cell Endocrinol. 1999 May 25;151(1-2):65–77. [PubMed] [Google Scholar]
  • Deprez J, Vertommen D, Alessi DR, Hue L, Rider MH. 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. [PubMed] [Google Scholar]
  • Nakatani K, Sakaue H, Thompson DA, Weigel RJ, Roth RA. Identification of a human Akt3 (protein kinase B gamma) which contains the regulatory serine phosphorylation site. Biochem Biophys Res Commun. 1999 Apr 21;257(3):906–910. [PubMed] [Google Scholar]
  • Brodbeck D, Cron P, Hemmings BA. A human protein kinase Bgamma with regulatory phosphorylation sites in the activation loop and in the C-terminal hydrophobic domain. J Biol Chem. 1999 Apr 2;274(14):9133–9136. [PubMed] [Google Scholar]
Cell Signalling Group, Ludwig Institute for Cancer Research, 91 Riding House Street, London W1P 8BT, U.K. bartvanh@ludwig.ucl.ac.uk
Cell Signalling Group, Ludwig Institute for Cancer Research, 91 Riding House Street, London W1P 8BT, U.K. bartvanh@ludwig.ucl.ac.uk

Abstract

Phosphoinositide 3-kinases (PI3Ks) generate specific inositol lipids that have been implicated in the regulation of cell growth, proliferation, survival, differentiation and cytoskeletal changes. One of the best characterized targets of PI3K lipid products is the protein kinase Akt or protein kinase B (PKB). In quiescent cells, PKB resides in the cytosol in a low-activity conformation. Upon cellular stimulation, PKB is activated through recruitment to cellular membranes by PI3K lipid products and phosphorylation by 3'-phosphoinositide-dependent kinase-1 (PDK1). Here we review the mechanism by which PKB is activated and the downstream actions of this multifunctional kinase. We also discuss the evidence that PDK1 may be involved in the activation of protein kinases other than PKB, the mechanisms by which this activity of PDK1 could be regulated and the possibility that some of the currently postulated PKB substrates targets might in fact be phosphorylated by PDK1-regulated kinases other than PKB.

Abstract
Full Text
Selected References
Collaboration tool especially designed for Life Science professionals.Drag-and-drop any entity to your messages.