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Shc coordinates signals from intercellular junctions and integrins to regulate flow-induced inflammation

¹ Department of Cell and Molecular Physiology, ² Program in Genetics and Molecular Biology, ³ Carolina Cardiovascular Biology Center, and ⁴ Department of Pathology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599

Correspondence to Ellie Tzima: etzima{at}med.unc.edu

Atherosclerotic plaques develop in regions of the vasculature associated with chronic inflammation due to disturbed flow patterns. Endothelial phenotype modulation by flow requires the integration of numerous mechanotransduction pathways, but how this is achieved is not well understood. We show here that, in response to flow, the adaptor protein Shc is activated and associates with cell–cell and cell–matrix adhesions. Shc activation requires the tyrosine kinases vascular endothelial growth factor receptor 2 and Src. Shc activation and its vascular endothelial cadherin (VE-cadherin) association are matrix independent. In contrast, Shc binding to integrins requires VE-cadherin but occurs only on specific matrices. Silencing Shc results in reduction in both matrix-independent and matrix-dependent signals. Furthermore, Shc regulates flow-induced inflammatory signaling by activating nuclear factor B–dependent signals that lead to atherogenesis. In vivo, Shc is activated in atherosclerosis-prone regions of arteries, and its activation correlates with areas of atherosclerosis. Our results support a model in which Shc orchestrates signals from cell–cell and cell–matrix adhesions to elicit flow-induced inflammatory signaling.

Abbreviations used in this paper: AP, atheroprone; AR, atheroresistant; BAEC, bovine aortic endothelial cell; CL, collagen; EC, endothelial cell; ERK, extracellular signal–regulated kinase; FN, fibronectin; LN, laminin; NFB, nuclear factor B; VE-cadherin, vascular endothelial cadherin; VEGFR2, vascular endothelial growth factor receptor 2; VTI, 4-[(4'-chloro-2'-fluoro)phenylamino]-6,7-dimethoxyquinazoline.

© 2008 Liu et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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ATHEROSCLEROSIS NEEDS SHC

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• Robinson, R. (2008). ATHEROSCLEROSIS NEEDS SHC. JCB 182: 2-2 [Full Text]  

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