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Evidence of a Functional Role for Interaction between ICAM-1 and Nonmuscle -Actinins in Leukocyte Diapedesis¹

Institut National de la Santé et de la Recherche Médicale, Unité 578, Grenoble, France, and Université Grenoble I, Groupe de Recherche sur le Cancer du Poumon, Institut Albert Bonniot, Grenoble, France

ICAM-1 is involved in both adhesion and extravasation of leukocytes to endothelium during inflammation. It has been shown that the ICAM-1 cytoplasmic domain is important for transendothelial migration of leukocytes but the precise molecular mechanisms involving the intracytoplasmic portion of ICAM-1 is not known. To characterize precisely the molecular scaffolding associated with ICAM-1, we have used the yeast two-hybrid system, and we have identified six different proteins interacting with the ICAM-1 cytoplasmic domain. In this study, we report that the two forms of nonmuscle -actinin (i.e., -actinin 1 and -actinin 4) associate with ICAM-1, and that these interactions are essential for leukocyte extravasation. These interactions were further confirmed by coimmunoprecipitation and immunofluorescence in endothelial cells and in ICAM-1-transfected Chinese hamster ovary cells. The function of these interactions was analyzed by point mutation of charged amino acids located on ICAM-1 cytoplasmic domain. We have identified three charged amino acids (arginine 480, lysine 481, and arginine 486) which are essential in the binding of -actinins to the ICAM-1 cytoplasmic tail. Mutation of these amino acids completely inhibited ICAM-1-mediated diapedesis. Experiments with siRNA inhibiting specifically -actinin 1 or -actinin 4 on endothelial cells indicated that -actinin 4 had a major role in this phenomenon. Thus, our data demonstrate that ICAM-1 directly interacts with cytoplasmic -actinin 1 and 4 and that this interaction is required for leukocyte extravasation.

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 the Association pour la Recherche sur le Cancer.

² Address correspondence and reprint requests to Dr. Alain Duperray, Institut National de la Santé et de la Recherche Médicale, Unité 578, Institut Albert Bonniot, Domaine de la Merci, 38706 La Tronche Cedex, France. E-mail address: Alain.Duperray{at}ujf-grenoble.fr

³ Abbreviations used in this paper: EC, endothelial cell; ERM, ezrin, radixin, moesin; fg, fibrinogen; siRNA, small-interfering RNA; -Gal, -galactosidase; CHO, Chinese hamster ovary; PMN, polymorphonuclear neutrophil; WT, wild type; IP, immunoprecipitation; PC, Pearson’s correlation.

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