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Science 31 January 1997:
Vol. 275. no. 5300, pp. 665 - 668
DOI: 10.1126/science.275.5300.665
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Reports

Direct Regulation of the Akt Proto-Oncogene Product by Phosphatidylinositol-3,4-bisphosphate

Thomas F. Franke, * David R. Kaplan, Lewis C. Cantley, Alex Toker dagger

The regulation of the serine-threonine kinase Akt by lipid products of phosphoinositide 3-kinase (PI 3-kinase) was investigated. Akt activity was found to correlate with the amount of phosphatidylinositol-3,4-bisphosphate (PtdIns-3,4-P2) in vivo, and synthetic PtdIns-3,4-P2 activated Akt both in vitro and in vivo. Binding of PtdIns-3,4-P2 occurred within the Akt pleckstrin homology (PH) domain and facilitated dimerization of Akt. Akt mutated in the PH domain was not activated by PI 3-kinase in vivo or by PtdIns-3,4-P2 in vitro, and it was impaired in binding to PtdIns-3,4-P2. Examination of the binding to other phosphoinositides revealed that they bound to the Akt PH domain with much lower affinity than did PtdIns-3,4-P2 and failed to increase Akt activity. Thus, Akt is apparently regulated by the direct interaction of PtdIns-3,4-P2 with the Akt PH domain.

T. F. Franke, ABL-Basic Research Program, National Cancer Institute-Frederick Cancer Research Facility and Development Center (NCI-FCRFDC), Frederick, MD 21702, USA; Montreal Neurological Institute, McGill University, PQ H3A 2B4, Canada; and Division of Signal Transduction, Beth Israel Hospital (BIH), Department of Cell Biology, Harvard Medical School (HMS), Boston, MA 02115, USA. E-mail: tfranke{at}bidmc.harvard.edu
D. R. Kaplan, ABL-Basic Research Program, NCI-FCRFDC, Frederick, MD 21702, USA; and Montreal Neurological Institute, McGill University, Montreal, PQ H3A 2B4, Canada.
L. C. Cantley and A. Toker, Division of Signal Transduction, BIH, Department of Cell Biology, HMS, Boston, MA 02115, USA.
*   To whom correspondence should be addressed.

dagger    Present address: Boston Biomedical Research Institute, Boston, MA 02114, USA.

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Structural Basis for the Co-activation of Protein Kinase B by T-cell Leukemia-1 (TCL1) Family Proto-oncoproteins.
D. Auguin, P. Barthe, C. Royer, M.-H. Stern, M. Noguchi, S. T. Arold, and C. Roumestand (2004)
J. Biol. Chem. 279, 35890-35902
   Abstract »    Full Text »    PDF »
Differential Activation of the Phosphatidylinositol 3'-Kinase/Akt Survival Pathway by Ionizing Radiation in Tumor and Primary Endothelial Cells.
D. Zingg, O. Riesterer, D. Fabbro, C. Glanzmann, S. Bodis, and M. Pruschy (2004)
Cancer Res. 64, 5398-5406
   Abstract »    Full Text »    PDF »
SHIP1 and Lyn Kinase Negatively Regulate Integrin {alpha}IIb{beta}3 Signaling in Platelets.
M. J. Maxwell, Y. Yuan, K. E. Anderson, M. L. Hibbs, H. H. Salem, and S. P. Jackson (2004)
J. Biol. Chem. 279, 32196-32204
   Abstract »    Full Text »    PDF »
Structural Basis of Membrane Targeting by the Phox Homology Domain of Cytokine-independent Survival Kinase (CISK-PX).
Y. Xing, D. Liu, R. Zhang, A. Joachimiak, Z. Songyang, and W. Xu (2004)
J. Biol. Chem. 279, 30662-30669
   Abstract »    Full Text »    PDF »
The Hepatitis E Virus Open Reading Frame 3 Protein Activates ERK through Binding and Inhibition of the MAPK Phosphatase.
A. Kar-Roy, H. Korkaya, R. Oberoi, S. K. Lal, and S. Jameel (2004)
J. Biol. Chem. 279, 28345-28357
   Abstract »    Full Text »    PDF »
Lipopolysaccharide-Induced Macrophage Inflammatory Response Is Regulated by SHIP.
H. Fang, R. A. Pengal, X. Cao, L. P. Ganesan, M. D. Wewers, C. B. Marsh, and S. Tridandapani (2004)
J. Immunol. 173, 360-366
   Abstract »    Full Text »    PDF »
The Prognostic Significance of Phosphatidylinositol 3-Kinase Pathway Activation in Human Gliomas.
A. Chakravarti, G. Zhai, Y. Suzuki, S. Sarkesh, P. M. Black, A. Muzikansky, and J. S. Loeffler (2004)
J. Clin. Oncol. 22, 1926-1933
   Abstract »    Full Text »    PDF »
Alternagin-C, a Disintegrin-like Protein, Induces Vascular Endothelial Cell Growth Factor (VEGF) Expression and Endothelial Cell Proliferation in Vitro.
M. R. Cominetti, C. H. B. Terruggi, O. H. P. Ramos, J. W. Fox, A. Mariano-Oliveira, M. S. De Freitas, C. C. Figueiredo, V. Morandi, and H. S. Selistre-de-Araujo (2004)
J. Biol. Chem. 279, 18247-18255
   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 »
Inactivation of Platelet-derived Growth Factor Receptor by the Tumor Suppressor PTEN Provides a Novel Mechanism of Action of the Phosphatase.
L. Mahimainathan and G. G. Choudhury (2004)
J. Biol. Chem. 279, 15258-15268
   Abstract »    Full Text »    PDF »
LIPID Arrays: New Tools in the Understanding of Membrane Dynamics and Lipid Signaling.
P. T. Ivanova, S. B. Milne, J. S. Forrester, and H. A. Brown (2004)
Mol. Interv. 4, 86-96
   Abstract »    Full Text »    PDF »
Lipoxins Inhibit Akt/PKB Activation and Cell Cycle Progression in Human Mesangial Cells.
D. Mitchell, K. Rodgers, J. Hanly, B. McMahon, H. R. Brady, F. Martin, and C. Godson (2004)
Am. J. Pathol. 164, 937-946
   Abstract »    Full Text »    PDF »
Transgenic Expression of Insulin Receptor Substrate 2 in Murine B Cells Alters the Cell Density-Dependence of IgE Production In Vitro and Enhances IgE Production In Vivo.
A. E. Kelly-Welch, H. Y. Wang, L.-M. Wang, J. H. Pierce, G. Jay, F. Finkelman, and A. D. Keegan (2004)
J. Immunol. 172, 2803-2810
   Abstract »    Full Text »    PDF »
The K1 Protein of Kaposi's Sarcoma-Associated Herpesvirus Activates the Akt Signaling Pathway.
C. C. Tomlinson and B. Damania (2004)
J. Virol. 78, 1918-1927
   Abstract »    Full Text »    PDF »
c-Kit-Mediated Overlapping and Unique Functional and Biochemical Outcomes via Diverse Signaling Pathways.
L. Hong, V. Munugalavadla, and R. Kapur (2004)
Mol. Cell. Biol. 24, 1401-1410
   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 »
Integrin-linked kinase regulates vascular morphogenesis induced by vascular endothelial growth factor.
Y. Kaneko, K. Kitazato, and Y. Basaki (2004)
J. Cell Sci. 117, 407-415
   Abstract »    Full Text »    PDF »
Membrane Recognition and Targeting by Lipid-Binding Domains.
J. P. DiNitto, T. C. Cronin, and D. G. Lambright (2003)
Sci. STKE 2003, re16
   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 »
Homeostasis and regeneration of the hematopoietic stem cell pool are altered in SHIP-deficient mice.
C. D. Helgason, J. Antonchuk, C. Bodner, and R. K. Humphries (2003)
Blood 102, 3541-3547
   Abstract »    Full Text »    PDF »
Migrating glioma cells activate the PI3-K pathway and display decreased susceptibility to apoptosis.
A. M. Joy, C. E. Beaudry, N. L. Tran, F. A. Ponce, D. R. Holz, T. Demuth, and M. E. Berens (2003)
J. Cell Sci. 116, 4409-4417
   Abstract »    Full Text »    PDF »
From the Cover: Insulin regulates the activity of forkhead transcription factor Hnf-3{beta}/Foxa-2 by Akt-mediated phosphorylation and nuclear/cytosolic localization.
C. Wolfrum, D. Besser, E. Luca, and M. Stoffel (2003)
PNAS 100, 11624-11629
   Abstract »    Full Text »    PDF »
OxLDL induces mitogen-activated protein kinase activation mediated via PI3-kinase/Akt in vascular smooth muscle cells.
M.-W. Chien, C.-S. Chien, L.-D. Hsiao, C.-H. Lin, and C.-M. Yang (2003)
J. Lipid Res. 44, 1667-1675
   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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