The guanine nucleotide exchange factor p63RhoGEF, a specific link between Gq/11-coupled receptor signaling and RhoA.
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 G(q) 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 G(q/11)-coupled receptors (M3-cholinoceptor, histamine H1 receptor) or GTPase-deficient mutants of G alpha(q) and G alpha11. We further demonstrate that active G alpha(q) or G alpha11, but not G alpha12 or G alpha13, strongly enhances p63RhoGEF-induced RhoA activation by direct protein-protein interaction with p63RhoGEF at its C-terminal half. Moreover, the activation of p63RhoGEF by G alpha(q/11) occurs independently of and in competition to the activation of the canonical G alpha(q/11) effector phospholipase C beta. Therefore, our results elucidate a new signaling pathway by which G alpha(q/11)-coupled receptors specifically induce Rho signaling through a direct interaction of activated G alpha(q/11) subunits with p63RhoGEF.
Lutz
Susanne
S
Institut für Pharmakologie und Toxikologie, Fakultät für Klinische Medizin Mannheim, Universität Heidelberg, Maybachstrasse 14-16, D-68169 Mannheim, Germany.
Freichel-Blomquist
Andrea
A
Yang
Yang
Y
Rümenapp
Ulrich
U
Jakobs
Karl H
KH
Schmidt
Martina
M
Wieland
Thomas
T
D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000502:physiology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000502:physiology*; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D054799:Phospholipase C beta; D064067:Rho Guanine Nucleotide Exchange Factors; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic; D010738:Type C Phospholipases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000502:physiology*
C475063:ARHGEF25 protein, human; D020662:Guanine Nucleotide Exchange Factors; D007527:Isoenzymes; D064067:Rho Guanine Nucleotide Exchange Factors; D010738:Type C Phospholipases; D054799:Phospholipase C beta; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020742:rhoA GTP-Binding Protein