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Vol. 17, Issue 11, 4686-4697, November 2006
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Departments of Microbiology and Biomedical Engineering, *Robert M. Berne Cardiovascular Research Center, and ||Mellon Prostate Cancer Research Center, University of Virginia, Charlottesville, VA 22908; Department of Medicine, University of California at San Diego, San Diego, CA 92103; and Laboratory for Thrombosis Research, Interdisciplinary Research Center, Katholieke Universiteit, Leuven Campus Kortrijk, 8500 Kortrijk, Belgium
Submitted April 10, 2006;
Revised July 25, 2006;
Accepted August 14, 2006
Monitoring Editor: Richard Hynes
Atherosclerotic plaque develops at sites of disturbed flow. We previously showed that flow activates endothelial cell integrins, which then bind to the subendothelial extracellular matrix (ECM), and, in cells on fibronectin or fibrinogen, trigger nuclear factor-
B activation. Additionally, fibronectin and fibrinogen are deposited into the subendothelial ECM at atherosclerosis-prone sites at early times. We now show that flow activates ECM-specific signals that establish patterns of integrin dominance. Flow induced 
2
1 activation in cells on collagen, but not on fibronectin or fibrinogen. Conversely, 51 and v3 are activated on fibronectin and fibrinogen, but not collagen. Failure of these integrins to be activated on nonpermissive ECM is because of active suppression by the integrins that are ligated. Protein kinase A is activated specifically on collagen and suppresses flow-induced v3 activation. Alternatively, protein kinase C is activated on fibronectin and mediates 21 suppression. Thus, integrins actively cross-inhibit through specific kinase pathways. These mechanisms may determine cellular responses to complex extracellular matrices.
The online version of this contains supplemental material at MBC Online (http://www.molbiolcell.org). This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E06-04-0289) on August 23, 2006.
Address correspondence to: Martin A. Schwartz (maschwartz{at}virginia.edu)
Abbreviations used: bFGF, basic fibroblast growth factor; BAE, bovine aortic endothelial; BSA, bovine serum albumin; CaMKII, calcium/calmodulin-dependent kinase II; Coll, collagen; Dab-2, disabled-2; eNOS, endothelial nitric-oxide synthase; ECM, extracellular matrix; FBS, fetal bovine serum; FG, fibrinogen; FN, fibronectin; GST, glutathione S-transferase; HA, hemagglutinin; PMA, phorbol 12-myristate 13-acetate; PIP3, phosphatidylinositol-3,4,5-trisphosphate; PI 3-kinase, phosphoinositide 3-kinase; PTB, phosphotyrosine binding domain; PK, protein kinase
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