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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:839.)
© 2004 American Heart Association, Inc.

Vascular Biology

Cleavage of Focal Adhesion Kinase in Vascular Smooth Muscle Cells Overexpressing Membrane-Type Matrix Metalloproteinases

Tomoko Shofuda; Ken-ichi Shofuda; Nicola Ferri; Richard D. Kenagy; Elaine W. Raines; Alexander W. Clowes

From the Division of Vascular Surgery (T.S., K.-i.S., R.D.K., A.W.C.), Department of Surgery, University of Washington School of Medicine, Seattle, Wash; and the Department of Pathology (N.F., E.W.R.), University of Washington, Seattle, Wash.

Correspondence to Dr Alexander W. Clowes, Division of Vascular Surgery, Department of Surgery, University of Washington School of Medicine, HSB BB442, Box 356410, 1959 NE Pacific Street, Seattle, WA 98195-6410. E-mail clowes{at}u.washington.edu

Background— Membrane-type matrix metalloproteinases (MT-MMPs) were initially identified as cell surface activators of MMP-2 (gelatinase A). We have reported that MT1-MMPs and MT3-MMPs are expressed by activated vascular smooth muscle cells (SMCs) and play a role in the regulation of cell function. Overexpression of MT-MMPs results in cell rounding, decreased adherence, and increased migration. Because integrin-mediated cell adhesion regulates these events, we have investigated the functional relationship between MT-MMPs and focal adhesion assembly.

Methods and Results— Using adenoviral vectors we show that overexpression of MT-MMPs reduces the number of focal contacts, whereas the cell surface expression of integrin subunits remains unchanged. The 125-kDa focal adhesion kinase (FAK) is cleaved resulting in a 90-kDa fragment under these conditions, and paxillin is partially dissociated from FAK after its cleavage. Pretreatment of cells with BB94, a synthetic MMP inhibitor, rescues cell adhesion and prevents changes in focal adhesions, supporting a potential role for MT-MMP enzymatic activities.

Conclusions— This study provides the first evidence that MT-MMPs are not only important in matrix degradation but also may affect the function of focal adhesions through FAK cleavage.

Key Words: MT1-MMP • integrin • focal adhesion kinase • cell adhesion

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