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Science 25 July 1997:
Vol. 277. no. 5325, pp. 567 - 570
DOI: 10.1126/science.277.5325.567
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Reports

Dual Role of Phosphatidylinositol-3,4,5-trisphosphate in the Activation of Protein Kinase B

David Stokoe, *dagger Leonard R. Stephens, Terry Copeland, Piers R. J. Gaffney, Colin B. Reese, Gavin F. Painter, Andrew B. Holmes, Frank McCormick, * Phillip T. Hawkins

Protein kinase B (PKB) is a proto-oncogene that is activated in signaling pathways initiated by phosphoinositide 3-kinase. Chromatographic separation of brain cytosol revealed a kinase activity that phosphorylated and activated PKB only in the presence of phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4,5)P3]. Phosphorylation occurred exclusively on threonine-308, a residue implicated in activation of PKB in vivo. PtdIns(3,4,5)P3 was determined to have a dual role: Its binding to the pleckstrin homology domain of PKB was required to allow phosphorylation by the upstream kinase and it directly activated the upstream kinase.

D. Stokoe and F. McCormick, Onyx Pharmaceuticals, 3031 Research Drive, Richmond, CA 94806, USA.
L. R. Stephens and P. T. Hawkins, Babraham Institute, Babraham, CB2 4AT, Cambridge, UK.
T. Copeland, ABL-Basic Research Program, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD 21702, USA.
P. R. J. Gaffney and C. B. Reese, Department of Chemistry, Kings College, London WC2R 2LS, UK.
G. F. Painter and A. B. Holmes, Department of Chemistry, Cambridge University, Cambridge CB2 3RA, UK.
*   Present address: University of California, San Francisco Cancer Research Institute, 2340 Sutter Street, San Francisco, CA 94115, USA.

dagger    To whom correspondence should be addressed. E-mail: stokoe{at}cc.ucsf.edu

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   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 »
Aerosol Delivery of Glucosylated Polyethylenimine/Phosphatase and Tensin Homologue Deleted on Chromosome 10 Complex Suppresses Akt Downstream Pathways in the Lung of K-ras Null Mice.
H. W. Kim, I. K. Park, C. S. Cho, K. H. Lee, G. R. Beck Jr., N. H. Colburn, and M. H. Cho (2004)
Cancer Res. 64, 7971-7976
   Abstract »    Full Text »    PDF »
7-Hydroxystaurosporine (UCN-01) Inhibition of Akt Thr308 but not Ser473 Phosphorylation: A Basis for Decreased Insulin-Stimulated Glucose Transport.
S. B. Kondapaka, M. Zarnowski, D. R. Yver, E. A. Sausville, and S. W. Cushman (2004)
Clin. Cancer Res. 10, 7192-7198
   Abstract »    Full Text »    PDF »
MUC1 Oncoprotein Activates the FOXO3a Transcription Factor in a Survival Response to Oxidative Stress.
L. Yin, L. Huang, and D. Kufe (2004)
J. Biol. Chem. 279, 45721-45727
   Abstract »    Full Text »    PDF »
SH2-B Promotes Insulin Receptor Substrate 1 (IRS1)- and IRS2-mediated Activation of the Phosphatidylinositol 3-Kinase Pathway in Response to Leptin.
C. Duan, M. Li, and L. Rui (2004)
J. Biol. Chem. 279, 43684-43691
   Abstract »    Full Text »    PDF »
Akt Kinase Activation Blocks Apoptosis in Intestinal Epithelial Cells by Inhibiting Caspase-3 after Polyamine Depletion.
H. M. Zhang, J. N. Rao, X. Guo, L. Liu, T. Zou, D. J. Turner, and J.-Y. Wang (2004)
J. Biol. Chem. 279, 22539-22547
   Abstract »    Full Text »    PDF »
The MUC1 Oncoprotein Activates the Anti-apoptotic Phosphoinositide 3-Kinase/Akt and Bcl-xL Pathways in Rat 3Y1 Fibroblasts.
D. Raina, S. Kharbanda, and D. Kufe (2004)
J. Biol. Chem. 279, 20607-20612
   Abstract »    Full Text »    PDF »
Akt2, a Novel Functional Link between p38 Mitogen-Activated Protein Kinase and Phosphatidylinositol 3-Kinase Pathways in Myogenesis.
I. Gonzalez, G. Tripathi, E. J. Carter, L. J. Cobb, D. A. M. Salih, F. A. Lovett, C. Holding, and J. M Pell (2004)
Mol. Cell. Biol. 24, 3607-3622
   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 »
Regulated Membrane Trafficking of the Insulin-Responsive Glucose Transporter 4 in Adipocytes.
R. T. Watson, M. Kanzaki, and J. E. Pessin (2004)
Endocr. Rev. 25, 177-204
   Abstract »    Full Text »    PDF »
Akt Activation in Platelets Depends on Gi Signaling Pathways.
S. Kim, J. Jin, and S. P. Kunapuli (2004)
J. Biol. Chem. 279, 4186-4195
   Abstract »    Full Text »    PDF »
Involvement of the PI 3-kinase signaling pathway in progression of colon adenocarcinoma.
K. Khaleghpour, Y. Li, D. Banville, Z. Yu, and S.-H. Shen (2004)
Carcinogenesis 25, 241-248
   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 »
SH2-B Is a Positive Regulator of Nerve Growth Factor-mediated Activation of the Akt/Forkhead Pathway in PC12 Cells.
X. Wang, L. Chen, T. J. Maures, J. Herrington, and C. Carter-Su (2004)
J. Biol. Chem. 279, 133-141
   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
   Abstract »    Full Text »    PDF »
Ceramide Disables 3-Phosphoinositide Binding to the Pleckstrin Homology Domain of Protein Kinase B (PKB)/Akt by a PKC{zeta}-Dependent Mechanism.
D. J. Powell, E. Hajduch, G. Kular, and H. S. Hundal (2003)
Mol. Cell. Biol. 23, 7794-7808
   Abstract »    Full Text »    PDF »
Promotion of Mitosis by Activated Protein Kinase B After DNA Damage Involves Polo-Like Kinase 1 and Checkpoint Protein CHFR.
E. Shtivelman (2003)
Mol. Cancer Res. 1, 959-969
   Abstract »    Full Text »    PDF »
Perifosine, a novel alkylphospholipid, inhibits protein kinase B activation.
S. B. Kondapaka, S. S. Singh, G. P. Dasmahapatra, E. A. Sausville, and K. K. Roy (2003)
Mol. Cancer Ther. 2, 1093-1103
   Abstract »    Full Text »    PDF »


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