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

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 s...

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Bibliographic Details
Published in:The Journal of biological chemistry 2005-07, Vol.280 (26), p.24680-24689
Main Authors: Nanda, Nisha, Bao, Ming, Lin, Hanna, Clauser, Karl, Komuves, Laszlo, Quertermous, Thomas, Conley, Pamela B., Phillips, David R., Hart, Matthew J.
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Biotin - chemistry
Blood Platelets - metabolism
Blotting, Western
Cell Communication
Cell Line
Cloning, Molecular
COS Cells
Cross-Linking Reagents - pharmacology
Cytoplasm - metabolism
DNA, Complementary - metabolism
Dose-Response Relationship, Drug
Electrophoresis, Polyacrylamide Gel
Endothelial Cells - metabolism
Epidermal Growth Factor - metabolism
Eptifibatide
Flow Cytometry
Humans
Immunoprecipitation
Mass Spectrometry
Molecular Sequence Data
Oligonucleotide Array Sequence Analysis
Peptides - chemistry
Peptides - pharmacology
Peroxidase - chemistry
Phosphorylation
Platelet Activation
Platelet Aggregation
Platelet Glycoprotein GPIIb-IIIa Complex - chemistry
Protein Binding
Protein Structure, Tertiary
Receptors, Cell Surface - biosynthesis
Receptors, Cell Surface - chemistry
Receptors, Cell Surface - physiology
Reverse Transcriptase Polymerase Chain Reaction
RNA - metabolism
RNA, Messenger - metabolism
Sequence Homology, Amino Acid
Serine - chemistry
Signal Transduction
Threonine - chemistry
Tissue Distribution
Transfection
Tyrosine - chemistry
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Summary: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 αIIbβ3 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 αIIbβ3-mediated platelet-platelet contacts.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M413411200