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(Received for publication, August 20, 1996)
From the Department of Pharmacology and the Molecular Cardiobiology
Program, The regulation of endothelial nitric oxide
synthase (eNOS) by phosphorylation is poorly understood. Here, we
demonstrate that eNOS is tyrosine-phosphorylated in bovine aortic
endothelial cells (BAEC) using 32P metabolic labeling
followed by phosphoamino acid analysis and by phosphotyrosine specific
Western blotting. Treatment of BAEC with hydrogen peroxide and the
protein tyrosine phosphatase inhibitor, sodium orthovanadate, increases
eNOS tyrosine phosphorylation. Utilizing a novel immunoNOS assay, the
increase in tyrosine phosphorylation is associated with a 50% decrease
in the specific activity of the enzyme. Because eNOS is localized in
plasmalemma caveolae, we examined if tyrosine phosphorylated eNOS
interacts with caveolin-1, the coat protein of caveolae.
Immunoprecipitation of eNOS from bovine lung microvascular endothelial
cells resulted in the co-precipitation of caveolin-1. Conversely,
immunoprecipitation of caveolin-1 resulted in the
co-precipitation of tyrosine-phosphorylated eNOS. Thus, tyrosine
phosphorylation is a novel regulatory mechanism for eNOS and caveolin-1
is the first eNOS-associated protein. Collectively, these observations
provide a novel regulatory mechanism for eNOS and suggest that tyrosine
phosphorylation may influence its activity, subcellular trafficking,
and interaction with other caveolin-interacting proteins in
caveolae.
Volume 271, Number 44,
Issue of November 1, 1996
pp. 27237-27240
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.
,
Department
of Pathology, Yale University School of Medicine, New
Haven, Connecticut 06536
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