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J. Biol. Chem., Vol. 276, Issue 21, 17625-17628, May 25, 2001
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From Endothelial nitric-oxide
synthase (eNOS) is an important regulatory enzyme in the cardiovascular
system catalyzing the production of NO from arginine. Multiple
protein kinases including Akt/PKB, cAMP-dependent protein
kinase (PKA), and the AMP-activated protein kinase (AMPK) activate eNOS
by phosphorylating Ser-1177 in response to various stimuli. During VEGF
signaling in endothelial cells, there is a transient increase in
Ser-1177 phosphorylation coupled with a decrease in Thr-495
phosphorylation that reverses over 10 min. PKC signaling in endothelial
cells inhibits eNOS activity by phosphorylating Thr-495 and
dephosphorylating Ser-1177 whereas PKA signaling acts in reverse by
increasing phosphorylation of Ser-1177 and dephosphorylation of Thr-495
to activate eNOS. Both phosphatases PP1 and PP2A are associated with
eNOS. PP1 is responsible for dephosphorylation of Thr-495 based on its
specificity for this site in both eNOS and the corresponding synthetic
phosphopeptide whereas PP2A is responsible for dephosphorylation of
Ser-1177. Treatment of endothelial cells with calyculin selectively
blocks PKA-mediated dephosphorylation of Thr-495 whereas okadaic acid selectively blocks PKC-mediated dephosphorylation of Ser-1177. These results show that regulation of eNOS activity involves
coordinated signaling through Ser-1177 and Thr-495 by multiple protein
kinases and phosphatases.
ACCELERATED PUBLICATION
Coordinated Control of Endothelial Nitric-oxide Synthase
Phosphorylation by Protein Kinase C and the
cAMP-dependent Protein Kinase*
,,,,
, and**
St. Vincent's Institute of Medical
Research, St. Vincent's Hospital, 41 Victoria Parade, Fitzroy,
Victoria 3065, the § Department of Biochemistry & Molecular
Biology, Monash University, Clayton, Victoria 3168, the
¶ Department of Nephrology, Austin & Repatriation Medical
Centre Heidelberg, Victoria 3084, and the School of
Biomedical Sciences, University of Newcastle, New South Wales
2308, Australia
*
This research was supported by grants from the NHMRC
Australia, National Heart Foundation, and Diabetes Australia.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.
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