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BASIC BIOLOGY

Endothelin 1 Stimulates ß₁Pix-Dependent Activation of Cdc42 Through the G_s Pathway

Division of Nephrology, Department of Medicine, Kidney Disease Center and Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226

To whom requests for reprints should be addressed at ¹ Division of Nephrology, Department of Medicine, Kidney Disease Center and Cardiovascular Research Center, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226. E-mail: sorokin{at}mcw.edu

Abstract

ß₁Pix (PAK-interacting exchange factor) is a recently identified guanine nucleotide exchange factor (GEF) for the Rho family small G protein Cdc42/Rac. On stimulation with extracellular signals, GEFs induce the exchange of guanosine diphosphate to guanosine triphosphate, resulting in the activation of the small guanosine 5C-triphosphatases. This activation enables the signal to propagate to downstream effectors. Herein, we show that G_s stimulation by cholera toxin increased Cdc42 activation by endothelin-1 (ET-1), whereas pertussis toxin had no effect. H-89, a protein kinase A (PKA) inhibitor, strongly inhibited Cdc42 activation by ET-1. Moreover, the overexpression of ß₁Pix enhanced ET-1–induced Cdc42 activation. The essential role of ß₁Pix in ET-1–induced Cdc42 activation was evidenced by the blocking of Cdc42 activation in cells expressing ß₁Pix mutant lacking the ability to bind PAK (ß₁Pix SH3m[W43K]) or mutant lacking GEF activity (ß₁PixDH). The overexpression of mutant lacking the pleckstrin homology domain ß₁PixPH, which is unable to bind phospholipids, had no effect on Cdc42 activation. These results demonstrate that ß₁Pix, along with PKA, plays a crucial role in the regulation of Cdc42 activation by ET-1.

Key Words: G proteins • Cdc42 • Pix • endothelin • mesangial cells

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