A novel bifunctional phospholipase c that is regulated by Galpha 12 and stimulates the Ras/mitogen-activated protein kinase pathway

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 intracellul...

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Bibliographic Details
Published in:The Journal of biological chemistry 2001-01, Vol.276 (4), p.2758-2765
Main Authors: Lopez, I, Mak, E C, Ding, J, Hamm, H E, Lomasney, J W
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Cloning, Molecular
DNA, Complementary - genetics
GTP-Binding Protein alpha Subunits, G12-G13
Heterotrimeric GTP-Binding Proteins - metabolism
Humans
Mitogen-Activated Protein Kinases - metabolism
Molecular Sequence Data
Phosphoinositide Phospholipase C
ras Proteins - metabolism
Sequence Homology, Amino Acid
Signal Transduction
Type C Phospholipases - genetics
Type C Phospholipases - metabolism
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Summary: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.
ISSN:0021-9258