Document Detail

Src kinase mediates phosphatidylinositol 3-kinase/Akt-dependent rapid endothelial nitric-oxide synthase activation by estrogen.
MedLine Citation:
PMID:  12431978     Owner:  NLM     Status:  MEDLINE    
17beta-Estradiol activates endothelial nitric oxide synthase (eNOS), enhancing nitric oxide (NO) release from endothelial cells via the phosphatidylinositol 3-kinase (PI3-kinase)/Akt pathway. The upstream regulators of this pathway are unknown. We now demonstrate that 17beta-estradiol rapidly activates eNOS through Src kinase in human endothelial cells. The Src family kinase specific-inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) abrogates 17beta-estradiol- but not ionomycin-stimulated NO release. Consistent with these results, PP2 blocked 17beta-estradiol-induced Akt phosphorylation but did not inhibit NO release from cells transduced with a constitutively active Akt. PP2 abrogated 17beta-estradiol-induced activation of PI3-kinase, indicating that the PP2-inhibitable kinase is upstream of PI3-kinase and Akt. A 17beta-estradiol-induced estrogen receptor/c-Src association correlated with rapid c-Src phosphorylation. Moreover, transfection of kinase-dead c-Src inhibited 17beta-estradiol-induced Akt phosphorylation, whereas constitutively active c-Src increased basal Akt phosphorylation. Estrogen stimulation of murine embryonic fibroblasts with homozygous deletions of the c-src, fyn, and yes genes failed to induce Akt phosphorylation, whereas cells maintaining c-Src expression demonstrated estrogen-induced Akt activation. Estrogen rapidly activated c-Src inducing an estrogen receptor, c-Src, and P85 (regulatory subunit of PI3-kinase) complex formation. This complex formation results in the successive activation of PI3-kinase, Akt, and eNOS with consequent enhanced NO release, implicating c-Src as a critical upstream regulator of the estrogen-stimulated PI3-kinase/Akt/eNOS pathway.
M Page Haynes; Lei Li; Diviya Sinha; Kerry S Russell; Koji Hisamoto; Roland Baron; Mark Collinge; William C Sessa; Jeffrey R Bender
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.     Date:  2002-11-12
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  278     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2003 Jan 
Date Detail:
Created Date:  2003-01-20     Completed Date:  2003-03-04     Revised Date:  2012-06-22    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2118-23     Citation Subset:  IM    
Section of Cardiovascular Medicine, Department of Pharmacology, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut 06536, USA.
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MeSH Terms
Adenoviridae / genetics
Blotting, Western
Cell Line
Cells, Cultured
Electrophoresis, Polyacrylamide Gel
Endoplasmic Reticulum / metabolism
Endothelium, Vascular / cytology
Enzyme Activation
Enzyme Inhibitors / pharmacology
Estrogens / metabolism*
Nitric Oxide / metabolism
Nitric Oxide Synthase / metabolism*
Nitric Oxide Synthase Type II
Nitric Oxide Synthase Type III
Phosphatidylinositol 3-Kinases / metabolism*
Precipitin Tests
Protein Binding
Protein-Serine-Threonine Kinases*
Proto-Oncogene Proteins / metabolism
Proto-Oncogene Proteins c-akt
Receptors, Estrogen / metabolism*
Signal Transduction
Time Factors
Tyrosine / metabolism
src-Family Kinases / metabolism*
Grant Support
Reg. No./Substance:
0/Enzyme Inhibitors; 0/Estrogens; 0/Proto-Oncogene Proteins; 0/Receptors, Estrogen; 10102-43-9/Nitric Oxide; 55520-40-6/Tyrosine; EC protein, human; EC Oxide Synthase; EC Oxide Synthase Type II; EC Oxide Synthase Type III; EC protein, mouse; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC Kinases; EC protein, human; EC Kinases; EC Proteins c-akt

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