Receptor-dependent RhoA activation in G12/G13-deficient cells -: Genetic evidence for an involvement of Gq/G11

被引:163
作者
Vogt, S
Grosse, R
Schultz, G
Offermanns, S
机构
[1] Heidelberg Univ, Inst Pharmacol, D-69120 Heidelberg, Germany
[2] Free Univ Berlin, Inst Pharmacol, D-14195 Berlin, Germany
关键词
D O I
10.1074/jbc.M304570200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The small GTPase RhoA is involved in the regulation of various cellular functions like the remodeling of the actin cytoskeleton and the induction of transcriptional activity. G-protein-coupled receptors (GPCRs), which are able to activate G(q)/G(11) and G(12)/G(13) are major upstream regulators of RhoA activity, and G(12)/G(13) have been shown to couple GPCRs to the activation of Rho by regulating the activity of a subfamily of RhoGEF proteins. However, the possible contribution of G(q)/G(11) to the regulation of RhoA activity via GPCRs is controversial. We have used a genetic approach to study the role of heterotrimeric G-proteins in the activation of RhoA via endogenous GPCRs. In pertussis toxin-treated G(alpha12)/G(alpha13)-deficient as well as in Galpha(q)/Galpha(11)-deficient mouse embryonic fibroblasts (MEFs), in which coupling of receptors is restricted to G(q)/G(11) and G(12)/G(13), respectively, receptor activation results in Rho activation. Rho activation induced by receptor agonists via G(q)/G(11) occurs with lower potency than Rho activation via G(12)/G(13). Activation of RhoA via G(q)/G(11) is not affected by the phospholipase-C blocker U73122 or the Ca2+-chelator BAPTA, but can be blocked by a dominant-negative mutant of the RhoGEF protein LARG. Our data clearly show that G(12)/G(13) as well as G(q)/G(11) alone can couple GPCRs to the rapid activation of RhoA. G(q)/G(11)-mediated RhoA activation occurs independently of phospholipase C-beta and appears to involve LARG.
引用
收藏
页码:28743 / 28749
页数:7
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