title: Regulation of RhoA signaling by the cAMP-dependent phosphorylation of RhoGDIα.
abstract: RhoA plays a pivotal role in regulating cell shape and movement. Protein kinase A (PKA) inhibits RhoA signaling and thereby induces a characteristic morphological change, cell rounding. This has been considered to result from cAMP-induced phosphorylation of RhoA at Ser-188, which induces a stable RhoA-GTP-RhoGDIα complex and sequesters RhoA to the cytosol. However, few groups have shown RhoA phosphorylation in intact cells. Here we show that phosphorylation of RhoGDIα but not RhoA plays an essential role in the PKA-induced inhibition of RhoA signaling and in the morphological changes using cardiac fibroblasts. The knockdown of RhoGDIα by siRNA blocks cAMP-induced cell rounding, which is recovered by RhoGDIα-WT expression but not when a RhoGDIα-S174A mutant is expressed. PKA phosphorylates RhoGDIα at Ser-174 and the phosphorylation of RhoGDIα is likely to induce the formation of a active RhoA-RhoGDIα complex. Our present results thus reveal a principal molecular mechanism underlying G(s)/cAMP-induced cross-talk with G(q)/G(13)/RhoA signaling.
authors.affiliation: Department of Endocrinology and Nephrology, The University of Tokyo School of Medicine, Tokyo 113-8655, Japan.
authors.forename: Atsuro
authors.initials: A
authors.lastname: Oishi
authors.forename: Noriko
authors.initials: N
authors.lastname: Makita
authors.forename: Junichiro
authors.initials: J
authors.lastname: Sato
authors.forename: Taroh
authors.initials: T
authors.lastname: Iiri
mesh_terms: D000818:Animals; D019556:COS Cells; D002417:Cattle; D002460:Cell Line; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D010766:Phosphorylation; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D034741:RNA, Small Interfering; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein