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A Novel and Critical Role for Tyrosine 663 in Platelet Endothelial Cell Adhesion Molecule-1 Trafficking and Transendothelial Migration ¹

Bidisha Dasgupta^*, Eric Dufour^*, Zahra Mamdouh^* and William A. Muller^2,

^* Department of Pathology and Laboratory Medicine, Weill Medical College of Cornell University, New York, NY 10021; and Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611

PECAM-1/CD31 is required for leukocyte transendothelial migration (TEM) under most inflammatory conditions. A critical pool of PECAM-1 resides in the lateral border recycling compartment (LBRC). During TEM, membrane from the LBRC is redirected to surround the leukocyte, and this targeted recycling per se is required for TEM. The cytoplasmic domain of PECAM-1 contains two tyrosine residues that have been implicated in PECAM-1 signaling in other cells but never examined in the context of TEM. We found that expression of PECAM-1 imparts on cells the ability to support TEM and that tyrosine 663 (but not tyrosine 686) is required. Furthermore, tyrosine 663 is required for PECAM-1 to efficiently enter and exit the LBRC. Most important, mutation of tyrosine 663 abolishes the ability of the endothelial cells to support targeted recycling of the LBRC. These data define a novel role for tyrosine 663 and suggest that it is part of a recognition motif for trafficking to and/or from the LBRC.

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 National Institute of Health Grants HL046489 and HL064774 (to W.A.M.) and predoctoral and postdoctoral fellowship (T32 AIO7621) (to B.D.).

² Address correspondence and reprint requests to Dr. William A. Muller, Department of Pathology, Feinberg School of Medicine, Northwestern University. Ward 3-140, 303 East Chicago Avenue, Chicago, IL 60611. E-mail address: wamuller{at}northwestern.edu

³ Abbreviations used in this paper: LBRC, lateral border recycling compartment; EGFP, enhanced GFP; HPF, high-powered field; SHP, Src homology region 2 domain-containing tyrosine phosphatase; TEM, transendothelial migration; VE, vascular endothelial; WT, wild type.

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