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(Circulation Research. 2008;102:1265.)
© 2008 American Heart Association, Inc.

Integrative Physiology

Ste20-Related Kinase SLK Phosphorylates Ser188 of RhoA to Induce Vasodilation in Response to Angiotensin II Type 2 Receptor Activation

Christophe Guilluy, Malvyne Rolli-Derkinderen, Laurent Loufrani, Anne Bourgé, Daniel Henrion, Luc Sabourin, Gervaise Loirand, Pierre Pacaud

From Inserm U915 (C.G., M.R.-D., A.B., G.L., P.P.); Faculté des Sciences, l’institut du thorax (C.G., M.R.-D., A.B., G.L., P.P.); Centre Hospitalier Universitaire Nantes, l’institut du thorax (G.L.), Nantes, France; Inserm U771 and Centre National de la Recherche Scientifique Unité Mixte de Recherche 6214 (L.L., D.H.), Faculté de Médecine Angers, France; University of Ottawa and Ottawa Health Research Institute (L.S.), Ontario, Canada.

Correspondence to Pierre Pacaud, Inserm U915, Faculté des Sciences, 2 rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3, France. E-mail pierre.pacaud{at}univ-nantes.fr

The small G protein Rho signaling pathways are recognized as major regulators of cardiovascular functions, and activation of Rho proteins appears to be a common component for the pathogenesis of hypertension and vascular proliferative disorders. Recent evidence suggests that modulation of Rho protein signaling by phosphorylation of Rho proteins provides an additional simple mechanism for coordinating Rho protein functions. Phosphorylation of RhoA by cAMP- or cGMP-activated kinase on Ser188 induces cytosolic sequestration of RhoA through increased interaction with guanine dissociation inhibitor, thereby resulting in inhibition of RhoA-dependent functions. Here we show that stimulation of angiotensin II (Ang II) type 2 receptor (AT₂R) in vascular smooth muscle cells induces Ser188 phosphorylation of RhoA independently of cAMP- or cGMP-activated kinase. We identify the Ser/Thr kinase Ste20-related kinase SLK as a new kinase phosphorylating RhoA on Ser188. Activation of the signaling cascade involving Src homology 2 domain–containing protein-tyrosine phosphatase 1, casein kinase II and SLK is responsible for RhoA phosphorylation and inhibition of RhoA-mediated arterial contraction induced by AT₂R activation. These results thus identify the molecular mechanism linking AT₂R to RhoA inhibition and vasodilation.

Key Words: Rho • signal transduction • phosphorylation • angiotensin II • vascular smooth muscle

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