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J. Biol. Chem., Vol. 278, Issue 33, 31020-31023, August 15, 2003

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Localized Cdc42 Activation, Detected Using a Novel Assay, Mediates Microtubule Organizing Center Positioning in Endothelial Cells in Response to Fluid Shear Stress^*

Eleni Tzima , William B. Kiosses , Miguel A. del Pozo  and Martin Alexander Schwartz ¶

From the Department of Cell Biology, Division of Vascular Biology, The Scripps Research Institute, La Jolla, California 92037

Fluid flow regulates morphology, physiology, and pathophysiology of vascular endothelial cells (reviewed in Ref. 1). The small GTPase Cdc42 mediates polarity in several systems including migrating cells and early embryos, which involve reorientation of the microtubule organizing center (MTOC) and Golgi apparatus toward the direction of movement. Here, we show that Cdc42 is activated by fluid shear stress and that activation is a consequence of integrins binding to extracellular matrix. A novel fluorescence energy transfer assay to visualize Cdc42 activation in single cells shows that Cdc42 activity is polarized in the direction of flow. Localized activation of Cdc42 as well as the activity of Par6 and protein kinase C direct the reorientation of the MTOC to a position on the downstream side of the nucleus relative to the direction of flow. Thus, shear-stimulated integrin dynamics induce polarized Cdc42 activity, which induces MTOC localization through the Par6-protein kinase C complex.

Received for publication, February 3, 2003 , and in revised form, April 28, 2003.

^* This work was supported by U. S. Public Health Service Grant PO1 HL48728. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

A Leukemia and Lymphoma Society Special Fellow (Grant 3347-02).

^¶ To whom correspondence should be addressed: Depts. of Microbiology and Biomedical Engineering, Cardiovascular Research Center, Mellon Prostate Cancer Research Center, University of Virginia, 415 Lane Rd., Charlottesville, VA 22908. E-mail: maschwartz{at}virginia.edu.

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