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A Novel Bifunctional Phospholipase C That Is Regulated by Gα12 and Stimulates the Ras/Mitogen-activated Protein Kinase Pathway
- Source :
- Journal of Biological Chemistry. 276:2758-2765
- Publication Year :
- 2001
- Publisher :
- Elsevier BV, 2001.
-
Abstract
- Three families of phospholipase C (PI-PLCbeta, gamma, and delta) are known to catalyze the hydrolysis of polyphosphoinositides such as phosphatidylinositol 4,5-bisphosphate (PIP(2)) 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. PLCepsilon 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. PLCepsilon hydrolyzes PIP(2), and this activity is stimulated selectively by a constitutively active form of the heterotrimeric G protein Galpha(12). PLCepsilon and a mutant (H1144L) incapable of hydrolyzing phosphoinositides promote formation of GTP-Ras. Thus PLCepsilon is a RasGEF. PLCepsilon, the mutant H1144L, and the isolated GEF domain activate the mitogen-activated protein kinase pathway in a manner dependent on Ras but independent of PIP(2) hydrolysis. Our findings demonstrate that PLCepsilon is a novel bifunctional enzyme that is regulated by the heterotrimeric G protein Galpha(12) and activates the small G protein Ras/mitogen-activated protein kinase signaling pathway.
- Subjects :
- DNA, Complementary
Molecular Sequence Data
Small G Protein
Biology
GTP-Binding Protein alpha Subunits, G12-G13
Biochemistry
Phosphoinositide Phospholipase C
Heterotrimeric G protein
Humans
Amino Acid Sequence
Cloning, Molecular
Protein kinase A
Molecular Biology
Diacylglycerol kinase
Sequence Homology, Amino Acid
Phospholipase C
Cell Biology
Heterotrimeric GTP-Binding Proteins
Cell biology
Type C Phospholipases
Second messenger system
ras Proteins
Guanine nucleotide exchange factor
Mitogen-Activated Protein Kinases
Signal transduction
Signal Transduction
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 276
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....1840829103f32046af14c09956fef27c