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Blood, 15 February 2004, Vol. 103, No. 4, pp. 1348-1355. Prepublished online as a Blood First Edition Paper on October 23, 2003; DOI 10.1182/blood-2003-06-1781. This Article Full Text (PDF) All Versions of this Article: 2003-06-1781v1 103/4/1348    most recent Alert me when this article is cited Alert me if a correction is posted 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 Prevost, N. Articles by Brass, L. F Search for Related Content PubMed PubMed Citation Articles by Prevost, N. Articles by Brass, L. F Social Bookmarking                   What's this? Submitted June 3, 2003 Accepted October 16, 2003 Signaling by ephrinB1 and Eph kinases in platelets promotes Rap1 activation, platelet adhesion and aggregation via effector pathways that do not require phosphorylation of ephrinB1 Nicolas Prevost, Donna S Woulfe, Massimiliano Tognolini, Takako Tanaka, Wenying Jian, Ryan R Fortna, Hong Jiang, and Lawrence F Brass* Medicine, University of Pennsylvania, Philadelphia, PA, USA * Corresponding author; email: brass{at}mail.med.upenn.edu. We have previously shown that platelets express two receptor tyrosine kinases, EphA4 and EphB1, and the Eph kinase ligand, ephrinB1, and proposed that transcellular Eph/ephrin interactions made possible by the onset of platelet aggregation promote the further growth and stability of the hemostatic plug. The present study examines how this might occur. The results show that clustering of either ephrinB1 or EphA4 causes platelets to adhere to immobilized fibrinogen via IIb3. Adhesion occurs more slowly than with ADP and requires PI 3-kinase and protein kinase C, but not ephrinB1 phosphorylation. By itself, Eph and ephrin signaling is insufficient to cause aggregation or the binding of soluble fibrinogen, but it can potentiate aggregation initiated by a Ca++ ionophore or by agonists for thrombin and thromboxane receptors. It also enhances Rap1 activation without requiring ADP secretion, ephrinB1 phosphorylation or the activation of PI 3-kinase and Src. From this we conclude that 1) Eph/ephrin signaling enhances the ability of platelet agonists to cause aggregation provided that those agonists can increase cytosolic Ca++, 2) this is accomplished in part by activating Rap1, and 3) these effects require oligomerization of ephrinB1, but not phosphotyrosine-based interactions with the ephrinB1 cytoplasmic domain. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: X. Su, J. Mi, J. Yan, P. Flevaris, Y. Lu, H. Liu, Z. Ruan, X. Wang, N. Kieffer, S. Chen, et al. RGT, a synthetic peptide corresponding to the integrin {beta}3 cytoplasmic C-terminal sequence, selectively inhibits outside-in signaling in human platelets by disrupting the interaction of integrin {alpha}IIb{beta}3 with Src kinase Blood, August 1, 2008; 112(3): 592 - 602. [Abstract] [Full Text] [PDF] L. F. Brass, L. Zhu, and T. J. Stalker Novel Therapeutic Targets at the Platelet Vascular Interface Arterioscler Thromb Vasc Biol, March 1, 2008; 28(3): s43 - s50. [Abstract] [Full Text] [PDF] D. Arvanitis and A. Davy Eph/ephrin signaling: networks Genes & Dev., February 15, 2008; 22(4): 416 - 429. [Abstract] [Full Text] [PDF] G. Jiang, T. Freywald, J. Webster, D. Kozan, R. Geyer, J. DeCoteau, A. Narendran, and A. Freywald In Human Leukemia Cells Ephrin-B-Induced Invasive Activity Is Supported by Lck and Is Associated with Reassembling of Lipid Raft Signaling Complexes Mol. Cancer Res., February 1, 2008; 6(2): 291 - 305. [Abstract] [Full Text] [PDF] D. Pfaff, U. Fiedler, and H. G. Augustin Emerging roles of the Angiopoietin-Tie and the ephrin-Eph systems as regulators of cell trafficking J. Leukoc. Biol., October 1, 2006; 80(4): 719 - 726. [Abstract] [Full Text] [PDF] G. Yu, J. Mao, Y. Wu, H. Luo, and J. Wu Ephrin-B1 Is Critical in T-cell Development J. Biol. Chem., April 14, 2006; 281(15): 10222 - 10229. [Abstract] [Full Text] [PDF] N. Nanda, P. Andre, M. Bao, K. Clauser, F. Deguzman, D. Howie, P. B. Conley, C. Terhorst, and D. R. Phillips Platelet aggregation induces platelet aggregate stability via SLAM family receptor signaling Blood, November 1, 2005; 106(9): 3028 - 3034. [Abstract] [Full Text] [PDF] N. Prevost, D. S. Woulfe, H. Jiang, T. J. Stalker, P. Marchese, Z. M. Ruggeri, and L. F. Brass Eph kinases and ephrins support thrombus growth and stability by regulating integrin outside-in signaling in platelets PNAS, July 12, 2005; 102(28): 9820 - 9825. [Abstract] [Full Text] [PDF] G. Serini and F. Bussolino Common Cues in Vascular and Axon Guidance Physiology, December 1, 2004; 19(6): 348 - 354. [Abstract] [Full Text] [PDF]

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