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J. Biol. Chem., Vol. 279, Issue 32, 33263-33272, August 6, 2004

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Mutagenesis of the Ezrin-Radixin-Moesin Binding Domain of L-selectin Tail Affects Shedding, Microvillar Positioning, and Leukocyte Tethering^*

Aleksandar Iveti, Oliver Florey¶, Jürgen Deka||**, Dorian O. Haskard¶, Ann Ager, and Anne J. Ridley

From the Ludwig Institute for Cancer Research, Royal Free and University College School of Medicine, 91 Riding House Street, London W1W 7BS United Kingdom, ^¶BHF Cardiovascular Medicine Unit, Imperial College, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom, the Divisions of ^||Protein Structure and Immune Cell Biology, The National Institute for Medical Research, London NW7 1AA, United Kingdom, and the Department of Biochemistry and Molecular Biology, University College, London WC1E 6BT, United Kingdom

L-selectin is a cell adhesion molecule that mediates the initial capture (tethering) and subsequent rolling of leukocytes along ligands expressed on endothelial cells. We have previously identified ezrin and moesin as novel binding partners of the 17-amino acid L-selectin tail, but the biological role of this interaction is not known. Here we identify two basic amino acid residues within the L-selectin tail that are required for binding to ezrin-radixinmoesin (ERM) proteins: arginine 357 and lysine 362. L-selectin mutants defective for ERM binding show reduced localization to microvilli and decreased phorbol 12-myristate 13-acetate-induced shedding of the L-selectin ectodomain. Cells expressing these L-selectin mutants have reduced tethering to the L-selectin ligand P-selectin glycoprotein ligand-1, but rolling velocity on P-selectin glycoprotein ligand-1 is not affected. These results suggest that ERM proteins are required for microvillar positioning of L-selectin and that this is important both for leukocyte tethering and L-selectin shedding.

Received for publication, November 7, 2003 , and in revised form, June 2, 2004.

^* This work was supported by the Ludwig Institute for Cancer Research and European Community Contract QLGI-CT-99-013036 (to A. A. and A. J. R.), the Medical Research Council (United Kingdom) (to A. A.), the British Heart Foundation (to O. F. and D. O. H.), and an EU Marie Curie Fellowship (to J. D.). 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.

^** Present address: ISREC, Chemin des Boveresses 155, 1066 Epalinges s/Lausanne, Switzerland.

To whom correspondence should be addressed. Tel.: 44-20-7878-4036; Fax: 44-20-7878-4040; E-mail: aleks{at}ludwig.ucl.ac.uk.

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