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J. Biol. Chem., Vol. 282, Issue 37, 27343-27353, September 14, 2007

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The Role of Receptor Oligomerization in Modulating the Expression and Function of Leukocyte Adhesion-G Protein-coupled Receptors^*

John Q. Davies¹, Gin-Wen Chang¹, Simon Yona, Siamon Gordon, Martin Stacey², and Hsi-Hsien Lin³

From the Sir William Dunn School of Pathology, University of Oxford, South Parks Rd., Oxford, OX1 3RE, United Kingdom and the Department of Microbiology and Immunology, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Rd., Kwei-San, Tao-Yuan, Taiwan

The human leukocyte adhesion-G protein-coupled receptors (GPCRs), the epidermal growth factor (EGF)-TM7 proteins, are shown here to function as homo- and hetero-oligomers. Using cell surface cross-linking, co-immunoprecipitation, and fluorescence resonance energy transfer analysis of EMR2, an EGF-TM7 receptor predominantly expressed in myeloid cells, we demonstrate that it forms dimers in a reaction mediated exclusively by the TM7 moiety. We have also identified a naturally occurring but structurally unstable EMR2 splice variant that acts as a dominant negative modulator by dimerizing with the wild type receptor and down-regulating its expression. Additionally, heterodimerization between closely related EGF-TM7 members is shown to result in the modulation of expression and ligand binding properties of the receptors. These findings suggest that receptor homo- and hetero-oligomerization play a regulatory role in modulating the expression and function of leukocyte adhesion-GPCRs.

Received for publication, May 17, 2007 , and in revised form, July 9, 2007.

^* This study was supported by research grants from the Nuffield Oxford Medical Fellowship (to J. Q. D.), grants from the British Heart Foundation and the Medical Research Council (both to S. G.), Chang Gung Memorial Hospital Grants CMRPD33008 and CMRPD140131 (to H-H. L.), and National Science Council-Taiwan Grant NSC95-2320-B-182-012 (to H-H. L.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S4.

¹ These authors contributed equally to this work.

² To whom correspondence may be addressed. E-mail: martin.stacey{at}path.ox.ac.uk.

³ To whom correspondence may be addressed. E-mail: hhlin{at}mail.cgu.edu.tw.

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