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J. Biol. Chem., Vol. 280, Issue 26, 24680-24689, July 1, 2005

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Platelet Endothelial Aggregation Receptor 1 (PEAR1), a Novel Epidermal Growth Factor Repeat-containing Transmembrane Receptor, Participates in Platelet Contact-induced Activation^*

Nisha Nanda, Ming Bao, Hanna Lin, Karl Clauser¶, Laszlo Komuves, Thomas Quertermous||, Pamela B. Conley, David R. Phillips, and Matthew J. Hart||**

From the ^||Donald W. Reynolds Cardiovascular Clinical Research Center, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, 94305, Portola Pharmaceuticals Incorporated, South San Francisco, California 94080, Millennium Pharmaceuticals Incorporated, South San Francisco, California 94080, and ^¶Millennium Pharmaceuticals Incorporated, Cambridge, Massachusetts 02139

The present study was designed to identify novel membrane proteins that signal during platelet aggregation. Because one putative mechanism for signaling by a membrane protein involves phosphorylation, we used oligonucleotide-based microarray analyses and mass spectrometric proteomics techniques to specifically discover membrane proteins and also identify those proteins that become phosphorylated on tyrosine, threonine, or serine residues upon platelet aggregation. Surprisingly, both techniques converged to identify a novel membrane protein we have termed PEAR1 (platelet endothelial aggregation receptor 1). Sequence analysis of PEAR1 predicts a type-1 membrane protein, 15 extracellular epidermal growth factor-like repeats, and multiple cytoplasmic tyrosines. Analysis of the tissue distribution of PEAR1 showed that it was most highly expressed in platelets and endothelial cells. Upon platelet aggregation induced by physiological agonists, PEAR1 became phosphorylated on tyrosine (Tyr-925), and serine (Ser-953 and Ser-1029) residues. PEAR1 tyrosine phosphorylation was blocked by eptifibatide, an _IIb3 antagonist, which inhibits platelet aggregation. Immune clustering of PEAR1 resulted in PEAR1 phosphorylation. Aggregation-induced PEAR1 tyrosine phosphorylation lead to the subsequent association with the ShcB adaptor protein. Platelet proximity induced by centrifugation also induced PEAR1 tyrosine phosphorylation, a reaction not inhibited by eptifibatide. These data suggest that PEAR1 is a novel platelet receptor that signals secondary to _IIb3-mediated platelet-platelet contacts.

Received for publication, November 29, 2004 , and in revised form, April 8, 2005.

^* 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.

^** To whom correspondence should be addressed: Division of Cardiovascular Medicine, Stanford University School of Medicine, Falk Bldg., CV184, 300 Pasteur Dr., Stanford, CA 94305. Tel.: 650-736-0640; Fax: 650-725-2178; E-mail: mhart{at}cvmed.stanford.edu.

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