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Science 23 January 1998:
Vol. 279. no. 5350, pp. 558 - 560
DOI: 10.1126/science.279.5350.558
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Reports

Role of Substrates and Products of PI 3-kinase in Regulating Activation of Rac-Related Guanosine Triphosphatases by Vav

Jaewon Han, Katherine Luby-Phelps, Balaka Das, Xiaodong Shu, Yi Xia, Raymond D. Mosteller, U. Murali Krishna, John R. Falck, Michael A. White, Daniel Broek *

Mitogen stimulation of cytoskeletal changes and c-jun amino-terminal kinases is mediated by Rac small guanine nucleotide-binding proteins. Vav, a guanosine diphosphate (GDP)-guanosine triphosphate (GTP) exchange factor for Rac that stimulates the exchange of bound GDP for GTP, bound to and was directly controlled by substrates and products of phosphoinositide (PI) 3-kinase. The PI 3-kinase substrate phosphatidylinositol-4,5-bisphosphate inhibited activation of Vav by the tyrosine kinase Lck, whereas the product phosphatidylinositol-3,4,5-trisphosphate enhanced phosphorylation and activation of Vav by Lck. Control of Vav in response to mitogens by the products of PI 3-kinase suggests a mechanism for Ras-dependent activation of Rac.

J. Han, B. Das, X. Shu, Y. Xia, R. D. Mosteller, D. Broek, Department of Biochemistry and Molecular Biology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90033-0800, USA.
K. Luby-Phelps and M. A. White, Department of Cell Biology and Neuroscience, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75235-9039, USA.
U. M. Krishna and J. R. Falck, Department of Biochemistry, University of Texas Southwestern Medical Center,
5323 Harry Hines Boulevard, Dallas, TX 75235-9039, USA.
*   To whom correspondence should be addressed. E-mail: broek{at}zygote.hsc.usc.edu

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I. Cascone, E. Audero, E. Giraudo, L. Napione, F. Maniero, M. R. Philips, J. G. Collard, G. Serini, and F. Bussolino (2003)
Blood 102, 2482-2490
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Truncation of C-mip (Tc-mip), a New Proximal Signaling Protein, Induces c-maf Th2 Transcription Factor and Cytoskeleton Reorganization.
P. Grimbert, A. Valanciute, V. Audard, A. Pawlak, S. Le gouvelo, P. Lang, P. Niaudet, A. Bensman, G. Guellaen, and D. Sahali (2003)
J. Exp. Med. 198, 797-807
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Leading the way: directional sensing through phosphatidylinositol 3-kinase and other signaling pathways.
S. Merlot and R. A. Firtel (2003)
J. Cell Sci. 116, 3471-3478
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Src Kinase Regulates the Activation of a Novel FGD-1-related Cdc42 Guanine Nucleotide Exchange Factor in the Signaling Pathway from the Endothelin A Receptor to JNK.
Y. Miyamoto, J. Yamauchi, and H. Itoh (2003)
J. Biol. Chem. 278, 29890-29900
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Critical Role of the Pleckstrin Homology Domain in Dbs Signaling and Growth Regulation.
E. J. Fuentes, A. E. Karnoub, M. A. Booden, C. J. Der, and S. L. Campbell (2003)
J. Biol. Chem. 278, 21188-21196
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Multifunctional Roles for the PH Domain of Dbs in Regulating Rho GTPase Activation.
K. L. Rossman, L. Cheng, G. M. Mahon, R. J. Rojas, J. T. Snyder, I. P. Whitehead, and J. Sondek (2003)
J. Biol. Chem. 278, 18393-18400
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