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J. Biol. Chem., Vol. 281, Issue 51, 39330-39338, December 22, 2006

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Lipid Rafts Facilitate the Interaction of PECAM-1 with the Glycoprotein VI-FcR -Chain Complex in Human Platelets^*

Fiona A. Lee¹, Marjolijn van Lier, Ingrid A. M. Relou, Loraine Foley, Jan-Willem N. Akkerman, Harry F. G. Heijnen^¶, and Richard W. Farndale²

From the Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, United Kingdom and the Laboratory for Thrombosis and Haemostasis, Department of Haematology, and the ^¶Cell Microscopy Centre and the Institute of Biomembranes, University Medical Centre, Utrecht, 3584 CX, Utrecht, the Netherlands

Glycoprotein (GP) VI, the main signaling receptor for collagen on platelets, is expressed in complex with the FcR -chain. The latter contains an immunoreceptor tyrosine-based activation motif, which becomes phosphorylated, initiating a signaling cascade leading to the rapid activation and aggregation of platelets. Previous studies have shown that signaling by immunoreceptor tyrosine-based activation motif-containing receptors is counteracted by signals from receptors with immunoreceptor tyrosine-based inhibitory motifs. Here we show, by immunoprecipitation, that the GPVI-FcR -chain complex associates with the immunoreceptor tyrosine-based inhibitory motif-containing receptor, PECAM-1. In platelets stimulated with collagen-related peptide (CRP-XL), tyrosine phosphorylation of PECAM-1 precedes that of the FcR -chain, implying direct regulation of the former. The GPVI-FcR -chain complex and PECAM-1 were present in both lipid raft and soluble fractions in human platelets; this distribution was unaltered by activation with CRP-XL. Their association occurred in lipid rafts and was lost after lipid raft depletion using methyl--cyclodextrin. We propose that lipid raft clustering facilitates the interaction of PECAM-1 with the GPVI-FcR -chain complex, leading to the down-regulation of the latter.

Received for publication, August 18, 2006 , and in revised form, October 10, 2006.

^* This work was supported by grants from the Dutch Heart Foundation, (to M. v. L.) and from Heart Research UK and the Medical Research Council UK (to L. F.). 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 Recipient of a British Heart Foundation studentship.

² To whom correspondence should be addressed: Dept. of Biochemistry, University of Cambridge, Downing Site, Cambridge CB2 1QW, United Kingdom. Tel.: 44-1223-766111; Fax: 44-1223-333345; E-mail: rwf10{at}cam.ac.uk.

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