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Science 9 October 1998:
Vol. 282. no. 5387, pp. 293 - 296
DOI: 10.1126/science.282.5387.293
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Reports

Bifurcation of Lipid and Protein Kinase Signals of PI3Kgamma to the Protein Kinases PKB and MAPK

Tzvetanka Bondeva, * Luciano Pirola, * Ginette Bulgarelli-Leva, Ignacio Rubio, Reinhard Wetzker, Matthias P. Wymann dagger

Phosphoinositide 3-kinases (PI3Ks) activate protein kinase PKB (also termed Akt), and PI3Kgamma activated by heterotrimeric guanosine triphosphate-binding protein can stimulate mitogen-activated protein kinase (MAPK). Exchange of a putative lipid substrate-binding site generated PI3Kgamma proteins with altered or aborted lipid but retained protein kinase activity. Transiently expressed, PI3Kgamma hybrids exhibited wortmannin-sensitive activation of MAPK, whereas a catalytically inactive PI3Kgamma did not. Membrane-targeted PI3Kgamma constitutively produced phosphatidylinositol 3,4,5-trisphosphate and activated PKB but not MAPK. Moreover, stimulation of MAPK in response to lysophosphatidic acid was blocked by catalytically inactive PI3Kgamma but not by hybrid PI3Kgamma s. Thus, two major signals emerge from PI3Kgamma : phosphoinositides that target PKB and protein phosphorylation that activates MAPK.

T. Bondeva, I. Rubio, R. Wetzker, Research Unit "Molecular Cell Biology," University of Jena, D-07747 Jena, Germany. L. Pirola, G. Bulgarelli-Leva, M. P. Wymann, Institute of Biochemistry, University of Fribourg, CH-1700 Fribourg, Switzerland.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed. E-mail: MatthiasPaul.Wymann{at}UniFR.ch

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J. Biol. Chem. 276, 1211-1219
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Potentiation of Smad Transactivation by Jun Proteins during a Combined Treatment with Epidermal Growth Factor and Transforming Growth Factor-beta in Rat Hepatocytes. ROLE OF PHOSPHATIDYLINOSITOL 3-KINASE-INDUCED AP-1 ACTIVATION.
P. Peron, M. Rahmani, Y. Zagar, A.-M. Durand-Schneider, B. Lardeux, and D. Bernuau (2001)
J. Biol. Chem. 276, 10524-10531
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Regulation of Gene Expression by Glucose in Pancreatic beta -Cells (MIN6) via Insulin Secretion and Activation of Phosphatidylinositol 3'-Kinase.
G. da Silva Xavier, A. Varadi, E. K. Ainscow, and G. A. Rutter (2000)
J. Biol. Chem. 275, 36269-36277
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A Critical Role for Phosphoinositide 3-Kinase Upstream of Gab1 and SHP2 in the Activation of Ras and Mitogen-activated Protein Kinases by Epidermal Growth Factor.
A. Yart, M. Laffargue, P. Mayeux, S. Chretien, C. Peres, N. Tonks, S. Roche, B. Payrastre, H. Chap, and P. Raynal (2001)
J. Biol. Chem. 276, 8856-8864
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Activation Loop Sequences Confer Substrate Specificity to Phosphoinositide 3-Kinase alpha (PI3Kalpha ). FUNCTIONS OF LIPID KINASE-DEFICIENT PI3Kalpha IN SIGNALING.
L. Pirola, M. J. Zvelebil, G. Bulgarelli-Leva, E. Van Obberghen, M. D. Waterfield, and M. P. Wymann (2001)
J. Biol. Chem. 276, 21544-21554
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Phosphorylation of p42/44MAPK by Various Signal Transduction Pathways Activates Cytosolic Phospholipase A2 to Variable Degrees.
G. S. A. T. van Rossum, R. Klooster, H. van den Bosch, A. J. Verkleij, and J. Boonstra (2001)
J. Biol. Chem. 276, 28976-28983
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The Roles of Phosphatidylinositol 3-Kinase and Protein Kinase Czeta for Thrombopoietin-induced Mitogen-activated Protein Kinase Activation in Primary Murine Megakaryocytes.
P. Rojnuckarin, Y. Miyakawa, N. E. Fox, J. Deou, G. Daum, and K. Kaushansky (2001)
J. Biol. Chem. 276, 41014-41022
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