Ste20-related kinase SLK phosphorylates Ser188 of RhoA to induce vasodilation in response to angiotensin II Type 2 receptor activation.
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 (AT(2)R) 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 AT(2)R activation. These results thus identify the molecular mechanism linking AT(2)R to RhoA inhibition and vasodilation.
Guilluy
Christophe
C
Inserm U915, Faculté des Sciences, l'nstitut du thorax, 2 rue de la Houssinière, BP 92208, 44322 Nantes Cedex 3, France.
Rolli-Derkinderen
Malvyne
M
Loufrani
Laurent
L
Bourgé
Anne
A
Henrion
Daniel
D
Sabourin
Luc
L
Loirand
Gervaise
G
Pacaud
Pierre
P
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000201:enzymology; D047390:Casein Kinase II / Q000378:metabolism; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D004997:Ethinyl Estradiol / Q000378:metabolism; D006973:Hypertension / Q000378:metabolism*; D008297:Male; D019290:Megestrol Acetate / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000502:physiology*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*; D000099317:Hippo Kinases
D000804:Angiotensin II; D047390:Casein Kinase II; D017868:Cyclic AMP-Dependent Protein Kinases; D017869:Cyclic GMP-Dependent Protein Kinases; D004997:Ethinyl Estradiol; D019290:Megestrol Acetate; D019001:Nitric Oxide Synthase; D017346:Protein Serine-Threonine Kinases; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D044139:Receptor, Angiotensin, Type 2; D014662:Vasoconstrictor Agents; D020742:rhoA GTP-Binding Protein; C026340:Oraconal; C481222:Slk protein, rat; D000099317:Hippo Kinases; C509250:Ptpn6 protein, rat