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J. Biol. Chem., Vol. 283, Issue 46, 31830-31839, November 14, 2008

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Filamin B Mediates ICAM-1-driven Leukocyte Transendothelial Migration^*

Edwin Kanters, Jos van Rijssel¹, Paul J. Hensbergen, David Hondius, Frederik P. J. Mul, André M. Deelder, Arnoud Sonnenberg^¶, Jaap D. van Buul², and Peter L. Hordijk, Fellow of the Landsteiner Foundation for Blood Transfusion Research supported by Grant 0112³

From the Department of Molecular Cell Biology, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Plesmanlaan 125, 1066 CX Amsterdam, the Biomolecular Mass Spectrometry Unit, Department of Parasitology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, and the ^¶Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands

During inflammation, the endothelium mediates rolling and firm adhesion of activated leukocytes. Integrin-mediated adhesion to endothelial ligands of the Ig-superfamily induces intracellular signaling in endothelial cells, which promotes leukocyte transendothelial migration. We identified the actin cross-linking molecule filamin B as a novel binding partner for intracellular adhesion molecule-1 (ICAM-1). Immune precipitation as well as laser scanning confocal microscopy confirmed the specific interaction and co-localization of endogenous filamin B with ICAM-1. Importantly, clustering of ICAM-1 promotes the ICAM-1-filamin B interaction. To investigate the functional consequences of filamin B binding to ICAM-1, we used small interfering RNA to reduce filamin B expression in ICAM-1-GFP expressing HeLa cells. We found that filamin B is required for the lateral mobility of ICAM-1 and for ICAM-1-induced transmigration of leukocytes. Reducing filamin B expression in primary human endothelial cells resulted in reduced recruitment of ICAM-1 to endothelial docking structures, reduced firm adhesion of the leukocytes to the endothelium, and inhibition of transendothelial migration. In conclusion, this study identifies filamin B as a molecular linker that mediates ICAM-1-driven transendothelial migration.

Received for publication, June 26, 2008 , and in revised form, September 2, 2008.

^* This work was supported in part by Dutch Heart Foundation Grant 2003B012. 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 and Videos 1–5.

¹ Supported by the Academic Medical Center, Amsterdam, The Netherlands.

² Supported by the Dutch Heart Foundation Grant 2005T039 and NWO Veni Grant 916.76.053.

³ To whom correspondence should be addressed: Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands. Tel.: 31-20-5123347; Fax: 31-20-5123474; E-mail: p.hordijk{at}sanquin.nl.

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