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Endothelial Cell Cortactin Coordinates Intercellular Adhesion Molecule-1 Clustering and Actin Cytoskeleton Remodeling during Polymorphonuclear Leukocyte Adhesion and Transmigration¹

Lin Yang^*, Jennifer R. Kowalski^,, Patrick Yacono, Milan Bajmoczi^,, Sunil K. Shaw^¶, Richard M. Froio^*, David E. Golan^,||, Sheila M. Thomas and Francis W. Luscinskas^2,*

^* Center for Excellence in Vascular Biology, Departments of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115; Departments of Medicine, Beth Israel-Deaconess Medical Center and Harvard Medical School, Boston, MA 02115; Biological and Biomedical Sciences Program, Harvard Medical School, Boston, MA 02115; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115; ^¶ Department of Pediatrics, Women and Infants Hospital, Providence, RI 02905; and ^|| Hematology Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115

Endothelial cell ICAM-1 interacts with leukocyte ₂ integrins to mediate adhesion and transmit outside-in signals that facilitate leukocyte transmigration. ICAM-1 redistribution and clustering appear necessary for leukocyte transmigration, but the mechanisms controlling ICAM-1 redistribution and clustering have not been identified. We recently reported that Src kinase phosphorylation of endothelial cortactin regulates polymorphonuclear cell (PMN) transmigration. In this study, we tested the hypotheses that the Src family kinase-cortactin pathway mediates association of ICAM-1 with the actin cytoskeleton and that this association is required for ICAM-1 clustering and leukocyte transmigration. Cross-linking ICAM-1 induced cytoskeletal remodeling and a decrease in ICAM-1 lateral mobility, as assessed by fluorescence recovery after photobleaching. Cytoskeletal remodeling after ICAM-1 cross-linking was reduced by knockdown of cortactin by small interfering RNA, by expression of a cortactin mutant deficient in Src phosphorylation sites (cortactin3F), and by the Src kinase inhibitor PP2. Pretreatment of cytokine-activated human endothelial monolayers with cortactin small interfering RNA significantly decreased both actin and ICAM-1 clustering around adherent PMN and the formation of actin-ICAM-1 clusters required for PMN transmigration. Our data suggest a model in which tyrosine phosphorylation of cortactin dynamically links ICAM-1 to the actin cytoskeleton, enabling ICAM-1 to form clusters and facilitate leukocyte transmigration.

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 These studies were supported by grants from the National Institutes of Health to F.W.L. (HL36028, HL53993, and HL56985) and D.E.G. (HL32854 and HL70819); an American Cancer Society grant (to S.M.T.); and a National Science Foundation predoctoral fellowship (to J.R.K.).

² Address correspondence and reprint requests to Dr. Francis W. Luscinskas, Brigham and Women’s Hospital, 77 Avenue Louis Pasteur, NRB752, Boston, MA 02115. E-mail address: fluscinskas{at}rics.bwh.harvard.edu

³ Abbreviations used in this paper: TEM, transendothelial migration; DIC, differential interference contrast; DPBS, Dulbecco’s PBS; FRAP, fluorescence recovery after photobleaching; iHUVEC, immortalized HUVEC; PMN, polymorphonuclear cell; siRNA, small interfering RNA.

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