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Blood, 1 February 2007, Vol. 109, No. 3, pp. 1018-1025. Prepublished online as a Blood First Edition Paper on September 26, 2006; DOI 10.1182/blood-2006-05-022301. This Article Full Text (PDF) All Versions of this Article: blood-2006-05-022301v1 109/3/1018    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 Kasirer-Friede, A. Articles by Shattil, S. J. Search for Related Content PubMed PubMed Citation Articles by Kasirer-Friede, A. Articles by Shattil, S. J. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 9, 2006 Accepted September 9, 2006 ADAP is required for normal IIb3 activation by VWF/GP Ib-IX-V and other agonists Ana Kasirer-Friede*, Paul Barry Moran, Jennifer Nagrampa-Orje, Ken Swanson, Zaverio M. Ruggeri, Burkhart Schraven, Benjamin G. Neel, Gary A. Koretzky, and Sanford J. Shattil Dept of Medicine, University of California San Diego, La Jolla, CA, United States Dept of Molecular & Experimental Medicine, The Scripps Research Institute, La Jolla, CA, United States Dept of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States Institute of Immunology, University of Magdeburg, Magdeburg, Germany Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA, United States * Corresponding author; email: akasirer{at}ucsd.edu. Interaction between von Willebrand factor (VWF) and platelet GP Ib-IX-V is required for hemostasis, in part because intracellular signals from VWF/GP Ib-IX-V activate the ligand-binding function of integrin IIb3. Since they also induce tyrosine phosphorylation of the ADAP adapter, we investigated ADAP's role in GP Ib-IX-V signal transduction. Fibrinogen or ligand-mimetic POW-2 Fab binding to IIb3 was stimulated by adhesion of ADAP+/+ murine platelets to dimeric VWF A1A2, but was significantly reduced in ADAP-/- platelets (P < 0.01). IIb3 activation by ADP or a Par4 thrombin receptor agonist was also decreased in ADAP-/- platelets. ADAP stabilized the expression of another adapter, SKAP-HOM, via interaction with latter's SH3 domain. However, no abnormalities in IIb3 activation were observed in SKAP-HOM-/- platelets, which express normal ADAP levels, further implicating ADAP as a modulator of IIb3 function. Under shear flow conditions over a combined matrix of VWF A1A2 and fibronectin to test interactions involving GP Ib-IX-V and IIb3, respectively, ADAP-/- platelets displayed reduced IIb3-dependent stable adhesion. Furthermore, ADAP-/- mice demonstrated increased re-bleeding from tail wounds. These studies establish ADAP as a necessary component of inside-out signaling pathways that couple GP Ib-IX-V and other platelet agonist receptors to IIb3 activation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: R. G. Baker, C. J. Hsu, D. Lee, M. S. Jordan, J. S. Maltzman, D. A. Hammer, T. Baumgart, and G. A. Koretzky The Adapter Protein SLP-76 Mediates "Outside-In" Integrin Signaling and Function in T Cells Mol. Cell. Biol., October 15, 2009; 29(20): 5578 - 5589. [Abstract] [Full Text] [PDF] H. Wang, B. Wei, G. Bismuth, and C. E. Rudd SLP-76-ADAP adaptor module regulates LFA-1 mediated costimulation and T cell motility PNAS, July 28, 2009; 106(30): 12436 - 12441. [Abstract] [Full Text] [PDF] N. Prevost, J. V. Mitsios, H. Kato, J. E. Burke, E. A. Dennis, T. Shimizu, and S. J. Shattil Group IVA cytosolic phospholipase A2 (cPLA2{alpha}) and integrin {alpha}IIb{beta}3 reinforce each other's functions during {alpha}IIb{beta}3 signaling in platelets Blood, January 8, 2009; 113(2): 447 - 457. [Abstract] [Full Text] [PDF] M. Dittrich, I. Birschmann, S. Mietner, A. Sickmann, U. Walter, and T. Dandekar Platelet Protein Interactions: Map, Signaling Components, and Phosphorylation Groundstate Arterioscler Thromb Vasc Biol, July 1, 2008; 28(7): 1326 - 1331. [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]

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