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Published on: November 26, 2018
Shc coordinates signals from intercellular junctions and integrins to regulate flow-induced inflammation.
Yunhao Liu1, Daniel Timothy Sweet, Mohamad Irani-Tehrani
1Department of Cell and Molecular Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
The Journal of Cell Biology
|July 9, 2008
Summary
The adaptor protein Shc plays a key role in atherosclerosis by integrating signals from blood flow to promote inflammation. Its activation in arteries correlates with disease severity, highlighting its potential as a therapeutic target.
Area of Science:
- Cardiovascular Biology
- Molecular Mechanisms of Disease
- Mechanotransduction
Background:
- Atherosclerosis is linked to chronic inflammation in blood vessels, driven by disturbed blood flow patterns.
- Endothelial cells respond to flow via mechanotransduction, but the integration of these pathways is unclear.
- The adaptor protein Shc's role in flow-induced endothelial responses is not well understood.
Purpose of the Study:
- To investigate the role of the adaptor protein Shc in endothelial response to disturbed blood flow.
- To elucidate the signaling pathways and adhesion molecules involved in Shc activation by flow.
- To determine Shc's contribution to flow-induced inflammatory signaling and atherogenesis.
Main Methods:
- Investigated Shc activation and association with cell adhesions (VE-cadherin, integrins) in endothelial cells under flow conditions.
- Utilized tyrosine kinase inhibitors (VEGFR2, Src) to study Shc activation requirements.
- Employed Shc silencing to assess its impact on signaling pathways (NF-κB) and matrix-dependent/independent signals.
- Examined Shc activation in atherosclerotic mouse arteries in vivo.
Main Results:
- Flow activates the adaptor protein Shc, which associates with cell-cell (VE-cadherin) and cell-matrix adhesions.
- Shc activation depends on VEGFR2 and Src tyrosine kinases and is partly matrix-independent.
- Shc silencing reduces both matrix-dependent and independent signals and inhibits flow-induced NF-κB activation.
- In vivo, Shc is activated in atherosclerosis-prone arterial regions, correlating with disease presence.
Conclusions:
- Shc acts as a crucial integrator of signals from cell-cell and cell-matrix adhesions in response to blood flow.
- Shc orchestrates flow-induced inflammatory signaling pathways, including NF-κB, contributing to atherogenesis.
- Targeting Shc may offer a novel therapeutic strategy for atherosclerosis by modulating vascular inflammation.
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