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Blood, 1 December 2005, Vol. 106, No. 12, pp. 3816-3823. Prepublished online as a Blood First Edition Paper on August 4, 2005; DOI 10.1182/blood-2005-03-0911. This Article Full Text Full Text (PDF) All Versions of this Article: 2005-03-0911v1 106/12/3816    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Wee, J. L. Articles by Jackson, D. E. Search for Related Content PubMed PubMed Citation Articles by Wee, J. L. Articles by Jackson, D. E. Related Collections Cell Adhesion and Motility Signal Transduction Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY The Ig-ITIM superfamily member PECAM-1 regulates the "outside-in" signaling properties of integrin IIb3 in platelets Janet L. Wee, and Denise E. Jackson From the Kronheimer Building, Austin Research Institute, Austin Health, Heidelberg, Victoria, Australia. Previous studies have implicated the immunoglobulin (Ig)–immunoreceptor tyrosine–based inhibitory motif (ITIM) superfamily member platelet endothelial cell adhesion molecule-1 (PECAM-1) in the regulation of integrin function. While PECAM-1 has been demonstrated to play a role as an inhibitory coreceptor of immunoreceptor tyrosine–based activation motif (ITAM)–associated Fc receptor IIa (FcRIIa) and glycoprotein VI (GPVI)/FcR -chain signaling pathways in platelets, its physiologic role in integrin IIb3–mediated platelet function is unclear. In this study, we investigate the functional importance of PECAM-1 in murine platelets. Using PECAM-1–deficient mice, we show that the platelets have impaired "outside-in" integrin IIb3 signaling with impaired platelet spreading on fibrinogen, failure to retract fibrin clots in vitro, and reduced tyrosine phosphorylation of focal adhesion kinase p125 (125FAK) following integrin IIb3–mediated platelet aggregation. This functional integrin IIb3 defect could not be attributed to altered expression of integrin IIb3. PECAM-1–/– platelets displayed normal platelet alpha granule secretion, normal platelet aggregation to protease-activated receptor-4 (PAR-4), adenosine diphosphate (ADP), and calcium ionophore, and static platelet adhesion. In addition, PECAM-1–/– platelets displayed normal "inside-out" integrin IIb3 signaling properties as demonstrated by normal agonist-induced binding of soluble fluoroscein isothiocyanate (FITC)–fibrinogen, JON/A antibody binding, and increases in cytosolic-free calcium and inositol (1,4,5)P3 triphosphate (IP3) levels. This study provides direct evidence that PECAM-1 is essential for normal integrin IIb3–mediated platelet function and that disruption of PECAM-1 induced a moderate "outsidein" integrin IIb3 signaling defect. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: D. Varga-Szabo, I. Pleines, and B. Nieswandt Cell Adhesion Mechanisms in Platelets Arterioscler. Thromb. Vasc. Biol., March 1, 2008; 28(3): 403 - 412. [Abstract] [Full Text] [PDF] Y. Wu, T. Welte, M. Michaud, and J. A. Madri PECAM-1: a multifaceted regulator of megakaryocytopoiesis Blood, August 1, 2007; 110(3): 851 - 859. [Abstract] [Full Text] [PDF] R. K. Andrews, D. Karunakaran, E. E. Gardiner, and M. C. Berndt Platelet Receptor Proteolysis: A Mechanism for Downregulating Platelet Reactivity Arterioscler. Thromb. Vasc. Biol., July 1, 2007; 27(7): 1511 - 1520. [Abstract] [Full Text] [PDF] T. S. Dhanjal, C. Pendaries, E. A. Ross, M. K. Larson, M. B. Protty, C. D. Buckley, and S. P. Watson A novel role for PECAM-1 in megakaryocytokinesis and recovery of platelet counts in thrombocytopenic mice Blood, May 15, 2007; 109(10): 4237 - 4244. [Abstract] [Full Text] [PDF]

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