Gα 13 mediates activation of the cytosolic phospholipase A 2α through fine regulation of ERK phosphorylation

Abstract

Heterotrimeric GTP-binding (G) proteins transduce hormone-induced signals to their effector enzymes, which include several phospholipases. In particular, the G o/G i and G q protein families have been shown to couple signaling to phospholipase A 2 (PLA 2), phospholipase C, and phospholipase D, while the G 12/G 13 family has been linked to the activation of small GTPases of the Rho family, and hence, to phospholipase D activation. Here, we demonstrate that in CHO cells, the G 12/G 13 family is also able to activate cPLA 2α, through the activation of RhoA and, subsequently, ERK1/2. Hormone-induced arachidonic acid release increased as a consequence of Gα 13 overexpression, and was inhibited through inhibition of Gα 13 signaling. The Gα 13-mediated cPLA 2α activation was inhibited by pharmacological blockade of ERK1/2 with either U0126 or PD98059, and by RhoA inactivation with C3 toxin or a dominant-negative RhoA (N19RhoA), and was stimulated by the serine–threonine phosphatase inhibitor calyculin A. Our data thus identify a pathway of cPLA 2α regulation that is initiated by thrombin and purinergic receptor activation, and that signals through Gα 13, RhoA and ERK1/2, with the involvement of a calyculin-sensitive phosphatase.