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Src kinase mediates phosphoinositide 3-kinase/Akt dependent rapid endothelial nitric oxide synthase activation by estrogen



Src kinase mediates phosphoinositide 3-kinase/Akt dependent rapid endothelial nitric oxide synthase activation by estrogen



FASEB Journal 16(4): A206



17beta-estradiol (E2) activates eNOS, enhancing NO release from endothelial cells via the PI3-kinase/Akt pathway. The upstream regulators of this pathway are unknown. We now demonstrate that the Src family kinase specific inhibitor PP2 abrogates E2- but not ionomycin-stimulated NO release. PP2 blocked E2-induced Akt phosphorylation, but did not inhibit NO release from cells transduced with a constitutively active Akt. Additionally, PP2 abrogated E2-induced production of PI3-kinase generated-phosphoinositides indicating that the PP2-inhibitable kinase is upstream of PI3-kinase and Akt. A demonstrated estrogen receptor-c-Src association correlated with rapid E2-induced c-Src phosphorylation. Moreover, transfection of a kinase-dead Src inhibited E2 induced Akt phosphorylation whereas constitutively active Src stimulated increased basal Akt phosphorylation. Collectively, these data demonstrate that E2 rapidly activates Src kinase resulting in successive activation of PI3-kinase, Akt and eNOS with consequent enhanced NO release. This implicates Src kinase as an important upstream regulator of the E2-stimulated endothelial PI3-kinase/Akt/eNOS pathway.

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Accession: 035762458

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