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J. Biol. Chem., Vol. 276, Issue 23, 19770-19777, June 8, 2001
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From the Among the drugs that are known to relax the
vascular smooth muscle and regulate other cellular functions,
Phosphorylation and Regulation of G-protein-activated
Phospholipase C-
3 by cGMP-dependent Protein Kinases*
,§,
Department of Medical Biochemistry and
Genetics, Center for Cancer Biology and Nutrition, Institute of
Biosciences and Technology, Texas A & M University System Health
Science Center, Houston, Texas 77030, the § Department of
Biology, Ocean University of Qingdao, Qingdao 266003, Peoples
Republic of China, and the ¶ Department of Biochemistry and
Molecular Biology, University of Texas Houston Medical School,
Houston, Texas 77030
-adrenergic agonists and nitric oxide-containing compounds are some
of the most effective ones. The mechanisms of these drugs are thought
to lower agonist-induced intracellular [Ca2+] by
increasing intracellular cAMP and cGMP, activating their respective
protein kinases. However, the physiological targets of cyclic
nucleotide-dependent protein kinases are not clear. The
molecular basis for the regulation of intracellular Ca2+ by
signaling pathways coupled to cyclic nucleotides is not well defined.
G-protein-activated phospholipase C (PLC-) catalyzes the hydrolysis
of phosphatidylinositol 4,5-bisphosphates to generate diacylglycerol
and inositol 1,4,5-triphosphate, leading to the activation of protein
kinase C and the mobilization of intracellular Ca2+. In
this study, we shown that G-protein-activated PLC enzymes are the
potential targets of cGMP-dependent protein kinases (PKG). PKG can directly phosphorylate PLC-2 and PLC-3 in
vitro with purified proteins and in vivo with
metabolic labeling. Phosphorylation of PLC- leads to the inhibition
of G-protein-activated PLC-3 activity by 50-70% in COS-7 cell
transfection assays. By using phosphopeptide mapping and site-directed
mutagenesis, we further identified two key phosphorylation sites for
the regulation of PLC-3 by PKG (Ser26 and
Ser1105). Mutation at these two sites (S26A and
S1105A) of PLC-3 completely blocked the phosphorylation of
PLC-3 protein catalyzed by PKG. Furthermore, mutation of these
serine residues removed the inhibitory effect of PKG on the activation
of the mutant PLC-3 proteins by G-protein subunits. Our results
suggest a molecular mechanism for the regulation of G-protein-mediated
intracellular [Ca2+] by the NO-cGMP-dependent
signaling pathway.
*
This work was supported in part by a Scientist Development
grant from the National American Heart Association, a Basil O'Connor Starter Scholar Research award from the March of Dimes Birth Defects Foundation (to M. L.), and National Institutes of Health Grant HD09618
(to B. M. S.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Institute of
Biosciences and Technology, Texas A & M University System Health Science Center, 2121 W. Holcombe Blvd., Houston, TX 77030. Tel.: 713-677-7505; Fax: 713-677-7512; E-mail: mliu@ibt.tamu.edu.
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