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Blood, 15 September 2005, Vol. 106, No. 6, pp. 1975-1981. Prepublished online as a Blood First Edition Paper on June 7, 2005; DOI 10.1182/blood-2005-01-0440. This Article Full Text (PDF) All Versions of this Article: 2005-01-0440v1 106/6/1975    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 Dai, K. Articles by Du, X. Search for Related Content PubMed PubMed Citation Articles by Dai, K. Articles by Du, X. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted February 1, 2005 Accepted May 20, 2005 A critical role for 14-3-3 protein in regulating the VWF binding function of platelet glycoprotein Ib-IX and its therapeutic implications Kesheng Dai, Richard Bodnar, Michael C Berndt, and Xiaoping Du* Department of Pharmacology, University of Illinois College of Medicine, Chicago, IL, USA Dept of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia * Corresponding author; email: xdu{at}uic.edu. The platelet receptor for von Willebrand factor (VWF), glycoprotein (GP) Ib-IX, mediates platelet adhesion and activation. The cytoplasmic domains of the GPIb and subunits contain binding sites for the phosphorylation-dependent signaling molecule, 14-3-3. Here we show that a novel membrane-permeable inhibitor of 14-3-3-GPIb interaction, MPC, potently inhibited VWF binding to platelets and VWF-mediated platelet adhesion under flow conditions. MPC also inhibited VWF-dependent platelet agglutination induced by ristocetin. Furthermore, activation of the VWF binding function of GPIb-IX induced by GPIb dephosphorylation is diminished by mutagenic disruption of the 14-3-3 binding site in the C-terminal domain of GPIb, mimicking MPC-induced inhibition, indicating that the inhibitory effect of MPC is likely to be caused by disruption of 14-3-3 binding to GPIb. These data suggest a novel 14-3-3-dependent regulatory mechanism that controls the VWF binding function of GPIb-IX, and also suggest a new type of anti-platelet agent that may be potentially useful in preventing or treating thrombosis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: Y. Yuan, W. Zhang, R. Yan, Y. Liao, L. Zhao, C. Ruan, X. Du, and K. Dai Identification of a Novel 14-3-3{zeta} Binding Site Within the Cytoplasmic Domain of Platelet Glycoprotein Ib{alpha} That Plays a Key Role in Regulating the von Willebrand Factor Binding Function of Glycoprotein Ib-IX Circ. Res., December 4, 2009; 105(12): 1177 - 1185. [Abstract] [Full Text] [PDF] H. Cheng, R. Yan, S. Li, Y. Yuan, J. Liu, C. Ruan, and K. Dai Shear-induced interaction of platelets with von Willebrand factor results in glycoprotein Ib{alpha} shedding Am J Physiol Heart Circ Physiol, December 1, 2009; 297(6): H2128 - H2135. [Abstract] [Full Text] [PDF] Y. Li, J. Lu, and E. V. Prochownik Modularity of the Oncoprotein-like Properties of Platelet Glycoprotein Ib{alpha} J. Biol. Chem., January 16, 2009; 284(3): 1410 - 1418. [Abstract] [Full Text] [PDF] 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] F.-T. Mu, R. K. Andrews, J. F. Arthur, A. D. Munday, S. L. Cranmer, S. P. Jackson, F. C. Stomski, A. F. Lopez, and M. C. Berndt A functional 14-3-3{zeta}-independent association of PI3-kinase with glycoprotein Ib{alpha}, the major ligand-binding subunit of the platelet glycoprotein Ib-IX-V complex Blood, May 1, 2008; 111(9): 4580 - 4587. [Abstract] [Full Text] [PDF] 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] H. Yin, A. Stojanovic, N. Hay, and X. Du The role of Akt in the signaling pathway of the glycoprotein Ib-IX induced platelet activation Blood, January 15, 2008; 111(2): 658 - 665. [Abstract] [Full Text] [PDF] S. Jain, M. Zuka, J. Liu, S. Russell, J. Dent, J. A. Guerrero, J. Forsyth, B. Maruszak, T. K. Gartner, B. Felding-Habermann, et al. Platelet glycoprotein Ib{alpha} supports experimental lung metastasis PNAS, May 22, 2007; 104(21): 9024 - 9028. [Abstract] [Full Text] [PDF] S.-Z. Luo, X. Mo, V. Afshar-Kharghan, S. Srinivasan, J. A. Lopez, and R. Li Glycoprotein Ib{alpha} forms disulfide bonds with 2 glycoprotein Ib{beta} subunits in the resting platelet Blood, January 15, 2007; 109(2): 603 - 609. [Abstract] [Full Text] [PDF] P. Nurden, N. Debili, W. Vainchenker, R. Bobe, R. Bredoux, E. Corvazier, R. Combrie, E. Fressinaud, D. Meyer, A. T. Nurden, et al. Impaired megakaryocytopoiesis in type 2B von Willebrand disease with severe thrombocytopenia Blood, October 15, 2006; 108(8): 2587 - 2595. [Abstract] [Full Text] [PDF] X. Mo, N. Lu, A. Padilla, J. A. Lopez, and R. Li The Transmembrane Domain of Glycoprotein Ibbeta Is Critical to Efficient Expression of Glycoprotein Ib-IX Complex in the Plasma Membrane J. Biol. Chem., August 11, 2006; 281(32): 23050 - 23059. [Abstract] [Full Text] [PDF]

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