The Guanine Nucleotide Exchange Factor p63RhoGEF, a Specific Link between Gq/11-coupled Receptor Signaling and RhoA

Abstract The monomeric GTPase RhoA, which is a key regulator of numerous cellular processes, is activated by a variety of G protein-coupled receptors, through either G12 or Gq family proteins. Here we report that p63RhoGEF, a recently identified RhoA-specific guanine nucleotide exchange factor, enhances the Rho-dependent gene transcription induced by agonist-stimulated Gq/11-coupled receptors (M3-cholinoceptor, histamine H1 receptor) or GTPase-deficient mutants of Gαq and Gα11. We further demonstrate that active Gαq or Gα11, but not Gα12 or Gα13, strongly enhances p63RhoGEF-induced RhoA activation by direct protein-protein interaction with p63RhoGEF at its C-terminal half. Moreover, the activation of p63RhoGEF by Gαq/11 occurs independently of and in competition to the activation of the canonical Gαq/11 effector phospholipase C β. Therefore, our results elucidate a new signaling pathway by which Gαq/11-coupled receptors specifically induce Rho signaling through a direct interaction of activated Gαq/11 subunits with p63RhoGEF.