Activation of PLEKHG2 RhoGEF by selective G beta gamma isoforms released from multiple classes of G proteins

Abstract

Listen

Translate article

PLEKHG2 is a novel Gβγ‐activated Rho guanine nucleotide exchange factor (GEF) which catalyzes the activation of the RhoGTPase family of proteins. Overexpression of PLEKHG2 has been associated with enhanced cell transformation. Additionally, PLEKHG2 may mediate lysophosphatidic acid (LPA)‐induced cell spreading. However; the mechanism of PLEKHG2 regulation has yet to be elucidated. In this study we aim to identify how LPA stimulation of G proteins activates PLEKHG2. Using a luciferase‐based reporter assay, we found that PLEKHG2 activation via LPA is selectively mediated by Gβγ subunits released from G proteins, as activation is completely abolished by scavengers of Gβγ, GαT or the C‐terminal tail of G protein‐coupled receptor kinase 2. Interestingly, PLEKHG2 activation is only partially inhibited by Pertussis toxin, the Gαq minigene, or the Gα13 minigene that selectively uncouple the Gi/o, Gq/11, and G12/13 classes of G proteins. The combination of these three inhibitors has additive effect on reducing activation, indicating that activation of PLEKHG2 involves Gβγ subunits released from multiple classes of G proteins. By comparing the activation of PLEKHG2 by different Gβ isoforms, we further provided evidence that activation of PLEKHG2 is Gβ isoform specific. Taken together, our data indicate that PLEKHG2 is a RhoGEF activated by selective Gβγ isoforms released from multiple classes of G proteins.