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J. Biol. Chem., Vol. 282, Issue 34, 25010-25019, August 24, 2007

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Membrane-type 1-Matrix Metalloproteinase Regulates Intracellular Adhesion Molecule-1 (ICAM-1)-mediated Monocyte Transmigration^*

Srinivas D. Sithu, William R. English¹, Paul Olson, Davia Krubasik², Andrew H. Baker^¶, Gillian Murphy³, and Stanley E. D'Souza⁴

From the Department of Physiology and Biophysics, University of Louisville, Louisville, Kentucky 40202, the Li Ka-Shing Centre, Cambridge Research Institute, Cancer Research UK, Robinson Way, Cambridge CB2 ORE, United Kingdom, and the ^¶Division of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8TA, United Kingdom

We examined the mechanism regulating intercellular cell adhesion molecule-1 (ICAM-1)-dependent monocyte transendothelial migration. Monocyte migration through endothelial cells expressing ICAM-1 alone was comparable to that of tumor necrosis factor--treated cells. Transmigration was reduced in ICAM-1 lacking the cytoplasmic tail and in tyrosine to alanine substitutions at Tyr-485 and Tyr-474. Tissue inhibitors of matrix metalloproteinases (TIMPs) -2 and -3 blocked transmigration, whereas TIMP-1 was ineffective. This profile suggested a role for membrane-type matrix metalloproteinases (MT-MMPs) in transmigration. Inhibitory antibodies and small interference RNA directed against MT1-MMP blocked transmigration, whereas overexpression of MT1-MMP in endothelial cells or monocytes promoted transmigration. MT1-MMP mediated the ectodomain cleavage of ICAM-1 that was blocked by TIMP-2 and -3. Overexpression of MT1-MMP rescued function in ICAM-1Y485A, and to a lesser extent in the cytoplasmic tail-deleted ICAM-1. In a binding assay, wild-type ICAM-1 bound to purified MT1-MMP while ICAM-1 mutants bound poorly. MT1-MMP co-localized with ICAM-1 at distinct structures in endothelial cells. MT1-MMP localization with cells expressing ICAM-1 mutations was reduced and diffused. These results indicate that the cytoplasmic tail of ICAM-1 regulates leukocyte transmigration through MT1-MMP interaction.

Received for publication, December 8, 2006 , and in revised form, June 13, 2007.

^* This work was supported in part by National Institutes of Health Grant PO1ES011860, the Jewish Hospital Foundation, Louisville (to S. E. D.), and an American Heart Association Postdoctoral Award (to S. D. S.) from the Ohio Valley Affiliate. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ Supported by the British Heart Foundation.

² Supported by the Deutscher Akademischer Austausch Deinst, Germany and Trinity College, Cambridge UK.

³ Supported by Cancer Research UK and the European Framework 6 Initiative (Grant LSHC-CT-2003-0503297).

⁴ To whom correspondence should be addressed: Dept. of Physiology and Biophysics, Health Sciences Center A-1115, University of Louisville, Louisville, KY 40292. Tel.: 502-852-3194; Fax: 502-852-6239; E-mail: sedsou01{at}louisville.edu.

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