PDZ‐RhoGEF and LARG are essential for embryo development, and provide a link between thrombin receptors and Rho activation

Abstract

G protein coupled receptors (GPCRs) linked to both members of the Gα12 family of heterotrimeric G proteins α subunits, Gα12 and Gα13, regulate the activation of Rho GTPases, thereby contributing to many key biological processes. Multiple Rho GEFs have been proposed to link Gα12/13 GPCRs to Rho activation. Among them, PDZ‐RhoGEF, leukemia‐associated Rho GEF (LARG) and p115‐RhoGEF (p115) share the presence of a regulator of G protein signaling‐homology (RGS) domain. There is limited information on the biological roles of this RGS‐containing family of RhoGEFs in vivo. Here, we investigated the biological role of two structurally related RhoGEFs: PDZ‐RhoGEF and LARG, by generating knockout mice. Although these mice do not display any overt phenotype, compound deficiency in PDZ‐RhoGEF and LARG leads to early embryonic lethality and to complex developmental defects. Signaling from Gα11/q‐linked GPCRs to Rho was not impaired in mouse embryonic fibroblasts defective in all 3 RGS‐containing RhoGEFs. However, combined lack of PDZ‐RhoGEF, LARG, and p115 expression abolished signaling through Gα12/13 to Rho, and thrombin‐induced cell proliferation, directional migration, and nuclear signaling through JNK and p38. These findings provide evidence of an essential role for the RGS‐containing RhoGEF family in signaling to Rho by Gα12/13‐coupled GPCRs, which may likely play a critical role during embryonic development.