Phospholipase Cepsilon is a nexus for Rho and Rap-mediated G protein-coupled receptor-induced astrocyte proliferation.
Phospholipase Cepsilon (PLCepsilon) has been suggested to transduce signals from small GTPases, but its biological function has not yet been clarified. Using astrocytes from PLCepsilon-deficient mice, we demonstrate that endogenous G protein-coupled receptors (GPCRs) for lysophosphatidic acid, sphingosine 1-phosphate, and thrombin regulate phosphoinositide hydrolysis primarily through PLCepsilon. Stimulation by lysophospholipids occurs through G(i), whereas thrombin activates PLC through Rho. Further studies reveal that PLCepsilon 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 PLCepsilon in this pathway can be explained by its role as a guanine nucleotide exchange factor for Rap1. Thus, PLCepsilon serves to transduce mitogenic signals through a mechanism distinct from its role in generation of PLC-derived second messengers.
Citro
Simona
S
Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA.
Malik
Sundeep
S
Oestreich
Emily A
EA
Radeff-Huang
Julie
J
Kelley
Grant G
GG
Smrcka
Alan V
AV
Brown
Joan Heller
JH
D000818:Animals; D001253:Astrocytes / Q000166:cytology* / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D049109:Cell Proliferation; D020558:GTP Phosphohydrolases / Q000378:metabolism; D005838:Genotype; D008246:Lysophospholipids / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D054801:Phosphoinositide Phospholipase C; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000502:physiology*; D020668:rap GTP-Binding Proteins / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000378:metabolism*
D008246:Lysophospholipids; D043562:Receptors, G-Protein-Coupled; D002217:Carbachol; D010738:Type C Phospholipases; D054801:Phosphoinositide Phospholipase C; C423320:phospholipase C epsilon; D020558:GTP Phosphohydrolases; D020668:rap GTP-Binding Proteins; D020741:rho GTP-Binding Proteins