Shc coordinates signals from intercellular junctions and integrins to regulate flow-induced inflammation.
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 kappaB-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.
Liu
Yunhao
Y
Department of Cell and Molecular Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Sweet
Daniel Timothy
DT
Irani-Tehrani
Mohamad
M
Maeda
Nobuyo
N
Tzima
Ellie
E
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001011:Aorta / Q000201:enzymology / Q000473:pathology; D015820:Cadherins / Q000378:metabolism; D002417:Cattle; D002460:Cell Line; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000201:enzymology; D006801:Humans; D007249:Inflammation / Q000201:enzymology*; D016023:Integrins / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007365:Intercellular Junctions / Q000201:enzymology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D012212:Rheology; D055765:Shc Signaling Adaptor Proteins; D015398:Signal Transduction; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013314:Stress, Mechanical; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D000099152:Cadherin 5
D048868:Adaptor Proteins, Signal Transducing; D015703:Antigens, CD; D015820:Cadherins; D016023:Integrins; D018799:Intercellular Adhesion Molecule-1; D020928:Mitogen-Activated Protein Kinases; D016328:NF-kappa B; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D019010:Vascular Cell Adhesion Molecule-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099152:Cadherin 5; C528024:SHC1 protein, human