A Novel Bifunctional Phospholipase C That Is Regulated by Gα 12 and Stimulates the Ras/Mitogen-activated Protein Kinase Pathway

Isabel Lopez, Eric C. Mak, Jirong Ding, Heidi E. Hamm, Jon W. Lomasney*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

224 Scopus citations


Three families of phospholipase C (PI-PLCβ, γ, and δ) are known to catalyze the hydrolysis of polyphosphoinositides such as phosphatidylinositol 4,5-bisphosphate (PIP2) to generate the second messengers inositol 1,4,5 trisphosphate and diacylglycerol, leading to a cascade of intracellular responses that result in cell growth, cell differentiation, and gene expression. Here we describe the founding member of a novel, structurally distinct fourth family of PI-PLC. PLCε not only contains conserved catalytic (X and Y) and regulatory domains (C2) common to other eukaryotic PLCs, but also contains two Ras-associating (RA) domains and a Ras guanine nucleotide exchange factor (RasGEF) motif. PLCε hydrolyzes PIP2, and this activity is stimulated selectively by a constitutively active form of the heterotrimeric G protein Gα12. PLCε and a mutant (H1144L) incapable of hydrolyzing phosphoinositides promote formation of GTP-Ras. Thus PLCε is a RasGEF. PLCε the mutant H1144L, and the isolated GEF domain activate the mitogen-activated protein kinase pathway in a manner dependent on Ras but independent of PIP2 hydrolysis. Our findings demonstrate that PLCε is a novel bifunctional enzyme that is regulated by the heterotrimeric G protein Gα12 and activates the small G protein Ras/mitogen-activated protein kinase signaling pathway.

Original languageEnglish (US)
Pages (from-to)2758-2765
Number of pages8
JournalJournal of Biological Chemistry
Issue number4
StatePublished - Jan 26 2001

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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