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Dual Role of Melanoma Cell Adhesion Molecule (MCAM)/CD146 in Lymphocyte Endothelium Interaction: MCAM/CD146 Promotes Rolling via Microvilli Induction in Lymphocyte and Is an Endothelial Adhesion Receptor¹

Borhane Guezguez^2,*, Pascale Vigneron^*, Nathalie Lamerant, Claudine Kieda, Thierry Jaffredo^* and Dominique Dunon^3,*

^* Université Pierre et Marie Curie–Paris 6, Unité Mixte de Recherche 7622, Centre National de la Recherche Scientifique (CNRS), Paris, France; and Unité Propre de Recherche 4301, CNRS–Centre de Biophysique Moléculaire, Orleans, France

The melanoma cell adhesion molecule (MCAM)/CD146 is expressed as two isoforms differing by their cytoplasmic domain (MCAM long (MCAM-l) and MCAM short (MCAM-s)). MCAM being expressed by endothelial cells and activated T cells, we analyzed its involvement in lymphocyte trafficking. The NK cell line NKL1 was transfected by MCAM isoforms and submitted to adhesion on both the endothelial cell monolayer and recombinant molecules under shear stress. MCAM-l transfection reduced rolling velocity and increased NKL1 adhesion on the endothelial cell monolayer and VCAM-1. Scanning electron microscopy revealed that MCAM-l induced microvilli formation and extension. In contrast, MCAM short or mock transfection had no effect on adhesion of NKL1 cells and microvilli formation. As shown by mutagenesis, serine 32 of the MCAM-l cytoplasmic tail, belonging to a putative protein kinase C phosphorylation site, was necessary for MCAM-l-actin cytoskeleton interaction and microvilli induction. Accordingly, chelerythrine chloride, a protein kinase C inhibitor, abolished MCAM-l-induced microvilli and rolling of MCAM-l-transfected NKL1 cells. Inhibition of adhesion under shear stress by anti-MCAM Abs suggested that both lymphoid MCAM-l and endothelial MCAM were also directly involved in lymphocyte endothelium interaction. MCAM-l-transfected NKL1 and activated CD4 T cells adhered to rMCAM under shear stress whereas anti-MCAM Ab treatment inhibited this process. Taken together, these data establish that MCAM is involved in the initial steps of lymphocyte endothelium interaction. By promoting the rolling on the inflammation marker VCAM-1 via microvilli induction and displaying adhesion receptor activity involving possible homophilic MCAM-l-MCAM-l interactions, MCAM might be involved in the recruitment of activated T cells to inflammation sites.

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.

¹ This work was supported by institutional funding from Centre National de la Recherche Scientifique and Université Pierre et Marie Curie as well as by grants from Association pour la Recherche contre le Cancer (ARC), La Ligue Nationale contre le Cancer, and Actions Concertées Incitatives of the Ministère de l’Éducation Nationale de la Recherche et de la Technologie (MENRT) and a grant of the Jérôme Lejeune Foundation (to C.K. and N.L.). B.G. was supported by MENRT, ARC, Société Française d’Hématologie, and Odette et Jean Duranton de Magny Fundation (Fondation de France) fellowships.

² Current address: McMaster Stem Cell and Cancer Research Institute, 1200 Main Street West, Michael G. DeGroote Centre for Learning and Discovery, 5077B, Hamilton, Ontario, Canada.

³ Address correspondence and reprint requests to Prof. Dominique Dunon, Université Pierre et Marie Curie, Paris 6, Unité Mixte de Recherche 7622, Centre National de la Recherche Scientifique, Bat C 6ème étage, Case 24, 9 quai St. Bernard, 75252 Paris Cedex 05, France. E-mail address: dunon{at}ccr.jussieu.fr

⁴ Abbreviations used in this paper: MCAM, melanoma cell adhesion molecule; MCAM-l, MCAM long; MCAM-s, MCAM short; OSEC, organ-specific endothelial cell; HAPEC, human appendix endothelial cell; HSkMEC, human skin microvascular endothelial cell; ERM, ezrin-radixin-moesin.

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