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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 Czeta 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 Czeta complex.

Original publication

DOI

10.1074/jbc.M301179200

Type

Journal article

Journal

J Biol Chem

Publication Date

15/08/2003

Volume

278

Pages

31020 - 31023

Keywords

Animals, Aorta, Cattle, Cell Polarity, Cells, Cultured, Endothelium, Vascular, Green Fluorescent Proteins, Indicators and Reagents, Integrins, Luminescent Proteins, Microtubule-Organizing Center, Protein Kinase C, Recombinant Fusion Proteins, Stress, Mechanical, cdc42 GTP-Binding Protein, rho GTP-Binding Proteins