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

Simona Citro, Sundeep Malik, Emily A. Oestreich, Julie Radeff-Huang, Grant G. Kelley, Alan V. Smrcka, Joan Heller Brown

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

Phospholipase Cε (PLCε) has been suggested to transduce signals from small GTPases, but its biological function has not yet been clarified. Using astrocytes from PLCε-deficient mice, we demonstrate that endogenous G protein-coupled receptors (GPCRs) for lysophosphatidic acid, sphingosine 1-phosphate, and thrombin regulate phosphoinositide hydrolysis primarily through PLCε. Stimulation by lysophospholipids occurs through Gi, whereas thrombin activates PLC through Rho. Further studies reveal that PLCε 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 PLCε in this pathway can be explained by its role as a guanine nucleotide exchange factor for Rap1. Thus, PLCε serves to transduce mitogenic signals through a mechanism distinct from its role in generation of PLC-derived second messengers.

Original languageEnglish
Pages (from-to)15543-15548
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number39
DOIs
Publication statusPublished - Sep 25 2007

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Type C Phospholipases
G-Protein-Coupled Receptors
Astrocytes
Thrombin
Lysophospholipids
Guanine Nucleotide Exchange Factors
Monomeric GTP-Binding Proteins
Nexus
Second Messenger Systems
Phosphatidylinositols
Hydrolysis
Cell Proliferation
DNA

Keywords

  • Guanine nucleotide exchange factor
  • Lysophospholipids
  • Mitogenesis
  • Small GTpases
  • Thrombin

ASJC Scopus subject areas

  • General
  • Genetics

Cite this

Phospholipase Cε is a nexus for Rho and Rap-mediated G protein-coupled receptor-induced astrocyte proliferation. / Citro, Simona; Malik, Sundeep; Oestreich, Emily A.; Radeff-Huang, Julie; Kelley, Grant G.; Smrcka, Alan V.; Brown, Joan Heller.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 39, 25.09.2007, p. 15543-15548.

Research output: Contribution to journalArticle

Citro, Simona ; Malik, Sundeep ; Oestreich, Emily A. ; Radeff-Huang, Julie ; Kelley, Grant G. ; Smrcka, Alan V. ; Brown, Joan Heller. / Phospholipase Cε is a nexus for Rho and Rap-mediated G protein-coupled receptor-induced astrocyte proliferation. In: Proceedings of the National Academy of Sciences of the United States of America. 2007 ; Vol. 104, No. 39. pp. 15543-15548.
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AU - Radeff-Huang, Julie

AU - Kelley, Grant G.

AU - Smrcka, Alan V.

AU - Brown, Joan Heller

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AB - Phospholipase Cε (PLCε) has been suggested to transduce signals from small GTPases, but its biological function has not yet been clarified. Using astrocytes from PLCε-deficient mice, we demonstrate that endogenous G protein-coupled receptors (GPCRs) for lysophosphatidic acid, sphingosine 1-phosphate, and thrombin regulate phosphoinositide hydrolysis primarily through PLCε. Stimulation by lysophospholipids occurs through Gi, whereas thrombin activates PLC through Rho. Further studies reveal that PLCε 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 PLCε in this pathway can be explained by its role as a guanine nucleotide exchange factor for Rap1. Thus, PLCε serves to transduce mitogenic signals through a mechanism distinct from its role in generation of PLC-derived second messengers.

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