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Published on: June 2, 2018
Variant estrogen receptor-c-Src molecular interdependence and c-Src structural requirements for endothelial NO
Lei Li1, Koji Hisamoto, Kyung Hee Kim
1Division of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06520, USA.
Summary
The tyrosine kinase c-Src is crucial for estrogen's protective effects on arteries. It facilitates nitric oxide production and vasorelaxation by interacting with estrogen receptors and eNOS in the cell membrane.
Area of Science:
- Cardiovascular Biology
- Molecular Endocrinology
- Cell Signaling
Background:
- The role of tyrosine kinase c-Src in systemic circulation and arterial responses to hormones like 17beta-estradiol (E2) is not well understood.
- c-Src is known to be essential in human endothelial cells for E2-stimulated activation of the phosphatidylinositol 3-kinase/Akt/endothelial NO synthase (eNOS) pathway, suggesting a role in vascular protection.
Purpose of the Study:
- To investigate the function of c-Src in the systemic circulation, specifically its involvement in estrogen-mediated arterial responses.
- To elucidate the mechanism by which c-Src influences nitric oxide (NO) production and vasorelaxation in response to E2.
Main Methods:
- Studies were conducted using murine aortas and human aortic and venous endothelial cells.
- Investigated the localization and conformation of c-Src, its interaction with estrogen receptor alpha variant ER46 and eNOS in the plasma membrane.
- Assessed the impact of c-Src on basal and E2-stimulated NO production and vasorelaxation.
Main Results:
- c-Src supports both basal and E2-stimulated NO production and is essential for E2-induced vasorelaxation in murine aortas.
- Only membrane-bound c-Src, in its "open" (substrate-accessible) conformation, is involved in E2-induced eNOS activation.
- c-Src associates with ER46 and eNOS in the plasma membrane, independent of its kinase activity.
- E2 activates c-Src via membrane ER46, leading to ER46 phosphorylation, subsequent membrane recruitment of ER46 and c-Src, and assembly of an eNOS-centered macrocomplex for membrane-initiated eNOS activation.
Conclusions:
- c-Src plays a critical role in estrogen-stimulated arterial responses, particularly in membrane-initiated rapid signal transduction.
- The substrate-accessible structure of c-Src is required for the assembly and localization of signaling complexes essential for eNOS activation.
- These findings reveal a novel mechanism for E2-mediated vascular protection involving c-Src and membrane-associated signaling pathways.
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