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Science 30 January 1998:
Vol. 279. no. 5351, pp. 710 - 714
DOI: 10.1126/science.279.5351.710
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Reports

Protein Kinase B Kinases That Mediate Phosphatidylinositol 3,4,5-Trisphosphate-Dependent Activation of Protein Kinase B

Len Stephens, * Karen Anderson, David Stokoe, Hediye Erdjument-Bromage, Gavin F. Painter, Andrew B. Holmes, Piers R. J. Gaffney, Colin B. Reese, Frank McCormick, Paul Tempst, J. Coadwell, Phillip T. Hawkins

Protein kinase B (PKB) is activated in response to phosphoinositide 3-kinases and their lipid products phosphatidylinositol 3,4,5-trisphosphate [PtdIns(3,4,5)P3] and PtdIns(3,4)P2 in the signaling pathways used by a wide variety of growth factors, antigens, and inflammatory stimuli. PKB is a direct target of these lipids, but this regulation is complex. The lipids can bind to the pleckstrin homologous domain of PKB, causing its translocation to the membrane, and also enable upstream, Thr308-directed kinases to phosphorylate and activate PKB. Four isoforms of these PKB kinases were purified from sheep brain. They bound PtdIns(3,4,5)P3 and associated with lipid vesicles containing it. These kinases contain an NH2-terminal catalytic domain and a COOH-terminal pleckstrin homologous domain, and their heterologous expression augments receptor activation of PKB, which suggests they are the primary signal transducers that enable PtdIns(3,4,5)P3 or PtdIns- (3,4)P2 to activate PKB and hence to control signaling pathways regulating cell survival, glucose uptake, and glycogen metabolism.

L. Stephens, K. Anderson, J. Coadwell, P. T. Hawkins, Inositide Laboratory, The Babraham Institute, Babraham, Cambridge CB2 4AT, UK.
D. Stokoe and F. McCormick, University of California, San Francisco, Cancer Research Institute, 2340 Sutter Street, San Francisco CA, 94115, USA.
H. Erdjument-Bromage and P. Tempst, Molecular Biology Program, Memorial Sloan-Kettering, Cancer Center, 1275 York Avenue, New York NY 10021, USA.
G. F. Painter and A. B. Holmes, Department of Chemistry, Cambridge University, Cambridge, UK.
P. R. J. Gaffney and C. B. Reese, Department of Chemistry, Kings College, London, UK.
*   To whom correspondence should be addressed. E-mail: len.stephens{at}bbsrc.ac.uk

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Spatio-temporal Dynamics of Protein Kinase B/Akt Signaling Revealed by a Genetically Encoded Fluorescent Reporter.
M. T. Kunkel, Q. Ni, R. Y. Tsien, J. Zhang, and A. C. Newton (2005)
J. Biol. Chem. 280, 5581-5587
   Abstract »    Full Text »    PDF »
Anti-CD63 antibodies suppress IgE-dependent allergic reactions in vitro and in vivo.
S. Kraft, T. Fleming, J. M. Billingsley, S.-Y. Lin, M.-H. Jouvin, P. Storz, and J.-P. Kinet (2005)
J. Exp. Med. 201, 385-396
   Abstract »    Full Text »    PDF »
Identification of Akt Pathway Inhibitors Using Redistribution Screening on the FLIPR and the IN Cell 3000 Analyzer.
B. K. Lundholt, V. Linde, F. Loechel, H.-C. Pedersen, S. Moller, M. Praestegaard, I. Mikkelsen, K. Scudder, S. P. Bjorn, M. Heide, et al. (2005)
J Biomol Screen 10, 20-29
   Abstract »    PDF »
Insulin potentiates AVP-induced AQP2 expression in cultured renal collecting duct principal cells.
M. Bustamante, U. Hasler, O. Kotova, A. V. Chibalin, D. Mordasini, M. Rousselot, A. Vandewalle, P.-Y. Martin, and E. Feraille (2005)
Am J Physiol Renal Physiol 288, F334-F344
   Abstract »    Full Text »    PDF »
Inhibition of Akt Kinase Activity by a Peptide Spanning the {beta}A Strand of the Proto-oncogene TCL1.
M. Hiromura, F. Okada, T. Obata, D. Auguin, T. Shibata, C. Roumestand, and M. Noguchi (2004)
J. Biol. Chem. 279, 53407-53418
   Abstract »    Full Text »    PDF »
Protein Kinase C {beta}II Regulates Akt Phosphorylation on Ser-473 in a Cell Type- and Stimulus-specific Fashion.
Y. Kawakami, H. Nishimoto, J. Kitaura, M. Maeda-Yamamoto, R. M. Kato, D. R. Littman, D. J. Rawlings, and T. Kawakami (2004)
J. Biol. Chem. 279, 47720-47725
   Abstract »    Full Text »    PDF »
Identification of a PKB/Akt Hydrophobic Motif Ser-473 Kinase as DNA-dependent Protein Kinase.
J. Feng, J. Park, P. Cron, D. Hess, and B. A. Hemmings (2004)
J. Biol. Chem. 279, 41189-41196
   Abstract »    Full Text »    PDF »
Involvement of 3-Phosphoinositide-dependent Protein Kinase-1 in the MEK/MAPK Signal Transduction Pathway.
S. Sato, N. Fujita, and T. Tsuruo (2004)
J. Biol. Chem. 279, 33759-33767
   Abstract »    Full Text »    PDF »
Neomycin Prevents the Wortmannin Inhibition of Insulin-stimulated Glut4 Translocation and Glucose Transport in 3T3-L1 Adipocytes.
D. J. James, C. Salaun, F. M. Brandie, J. M. C. Connell, and L. H. Chamberlain (2004)
J. Biol. Chem. 279, 20567-20570
   Abstract »    Full Text »    PDF »
SH2-containing Inositol Phosphatase 2 Predominantly Regulates Akt2, and Not Akt1, Phosphorylation at the Plasma Membrane in Response to Insulin in 3T3-L1 Adipocytes.
T. Sasaoka, T. Wada, K. Fukui, S. Murakami, H. Ishihara, R. Suzuki, K. Tobe, T. Kadowaki, and M. Kobayashi (2004)
J. Biol. Chem. 279, 14835-14843
   Abstract »    Full Text »    PDF »
Ribosomal S6 Kinase (RSK) Regulates Phosphorylation of Filamin A on an Important Regulatory Site.
M. S. Woo, Y. Ohta, I. Rabinovitz, T. P. Stossel, and J. Blenis (2004)
Mol. Cell. Biol. 24, 3025-3035
   Abstract »    Full Text »    PDF »
Regulation of Apoptosis by the Ft1 Protein, a New Modulator of Protein Kinase B/Akt.
I. Remy and S. W. Michnick (2004)
Mol. Cell. Biol. 24, 1493-1504
   Abstract »    Full Text »    PDF »
Atypical protein kinase C (PKC{zeta}/{lambda}) is a convergent downstream target of the insulin-stimulated phosphatidylinositol 3-kinase and TC10 signaling pathways.
M. Kanzaki, S. Mora, J. B. Hwang, A. R. Saltiel, and J. E. Pessin (2004)
J. Cell Biol. 164, 279-290
   Abstract »    Full Text »    PDF »
Agonist-specific Transactivation of Phosphoinositide 3-Kinase Signaling Pathway Mediated by the Dopamine D2 Receptor.
V. D. Nair and S. C. Sealfon (2003)
J. Biol. Chem. 278, 47053-47061
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Pyk2- and Src-Dependent Tyrosine Phosphorylation of PDK1 Regulates Focal Adhesions.
Y. Taniyama, D. S. Weber, P. Rocic, L. Hilenski, M. L. Akers, J. Park, B. A. Hemmings, R. W. Alexander, and K. K. Griendling (2003)
Mol. Cell. Biol. 23, 8019-8029
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Kinetic Analysis of Platelet-derived Growth Factor Receptor/Phosphoinositide 3-Kinase/Akt Signaling in Fibroblasts.
C. S. Park, I. C. Schneider, and J. M. Haugh (2003)
J. Biol. Chem. 278, 37064-37072
   Abstract »    Full Text »    PDF »
Transformation of Mammary Epithelial Cells by 3-Phosphoinositide- dependent Protein Kinase-1 Activates {beta}-Catenin and c-Myc, and Down-Regulates Caveolin-1.
Z. Xie, X. Zeng, T. Waldman, and R. I. Glazer (2003)
Cancer Res. 63, 5370-5375
   Abstract »    Full Text »    PDF »
Lipid Raft Targeting of the TC10 Amino Terminal Domain Is Responsible for Disruption of Adipocyte Cortical Actin.
J. Chunqiu Hou and J. E. Pessin (2003)
Mol. Biol. Cell 14, 3578-3591
   Abstract »    Full Text »    PDF »
Hyperosmotic-induced Protein Kinase N 1 Activation in a Vesicular Compartment Is Dependent upon Rac1 and 3-Phosphoinositide-dependent Kinase 1.
N. E. Torbett, A. Casamassima, and P. J. Parker (2003)
J. Biol. Chem. 278, 32344-32351
   Abstract »    Full Text »    PDF »
Integration of DAG signaling systems mediated by PKC-dependent phosphorylation of RasGRP3.
C. Teixeira, S. L. Stang, Y. Zheng, N. S. Beswick, and J. C. Stone (2003)
Blood 102, 1414-1420
   Abstract »    Full Text »    PDF »


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