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ATHEROSCLEROSIS NEEDS SHC

Knockdown of Shc (bottom) prevents adhesion of monocytes (green) to endothelial cells.

Liu et al. find that an adaptor protein called Shc orchestrates the response of endothelial cells to stress caused by turbulent blood flow.

In endothelial cells, alterations in blood flow are sensed by cell–cell junctions and cell–matrix adhesions, which can trigger inflammation and the formation of atherosclerotic plaques. The adaptor protein Shc, which is expressed in the endothelium, regulates responses to mechanical forces at the cell surface, leading the authors to explore its involvement in endothelial inflammation.

They now find that Shc becomes phosphorylated (and activated) primarily in areas of turbulent blood flow. Active Shc was found both at cell–cell junctions, in a complex with VE-cadherin and VEGFR2, and at cell–matrix adhesions where it associated with integrins in a cadherin-dependent manner. But Shc's arrival at adhesions was delayed for 30 minutes after the onset of shear stress, suggesting that signaling from cell–cell contacts may occur first and control the cell's interactions with the matrix.

Knockdown of Shc expression with siRNA suppressed signals from both cell–cell junctions and adhesions. As the latter signals activate the pro-inflammatory transcription factor NF-B, the lack of Shc blocked the expression of two NF-B–dependent atherosclerotic genes that encode the leukocyte-specific adhesion molecules VCAM-1 and ICAM-1. Endothelial cells were therefore unable to bind monocytes—the cells that trigger plaque formation when they ingest fat.

The intriguing delay between the appearance of phosphorylated Shc at cell–cell junctions and matrix adhesion sites is still unexplained: "We don't know whether there are two pools of Shc, or whether it translocates from cell–cell junctions to adhesions," says Tzima.

Liu, Y., et al. 2008. J. Cell Biol. doi:10.1083/jcb.200709176.[Abstract/Free Full Text]

Richard Robinson

rrobinson{at}nasw.org

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This Article Full Text (PDF, 913K) PPT slides of all figures Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Robinson, R. Search for Related Content PubMed Articles by Robinson, R. Social Bookmarking                            What's this?