Phospholipase Cε is a nexus for Rho and Rap-mediated G protein-coupled receptor-induced astrocyte proliferation

Phospholipase C epsilon (PLC epsilon) has been suggested to transduce signals from small GTPases, but its biological function has not, yet been clarified. Using astrocytes from PLC epsilon-deficient mice, we demonstrate that endogenous G protein-coupled receptors (GPCRs) for lysophosphaticlic acid, sphingosine 1-phosphate, and thrombin regulate phosphoinositide hydrolysis primarily through PLCE. Stimulation by lysophospholipids occurs through G(i), whereas thrombin activates PLC through Rho. Further studies reveal that PLCe is required for thrombin- but not LPA-induced sustained ERK activation and DNA synthesis, providing a novel mechanism for GPCR and Rho signaling to cell proliferation. The requirement for PLC epsilon in this pathway can be explained by its role as a guanine nucleotide exchange factor for Rap1. Thus, PLC epsilon serves to transduce mitogenic signals through a mechanism distinct from its role in generation of PLC-derived second messengers.