SEARCH:   Advanced

Blood, 1 September 2004, Vol. 104, No. 5, pp. 1327-1334. Prepublished online as a Blood First Edition Paper on April 1, 2004; DOI 10.1182/blood-2003-10-3633. This Article Full Text Full Text (PDF) All Versions of this Article: 2003-10-3633v1 104/5/1327    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 Kerrigan, S. W. Articles by Leavitt, A. D. Search for Related Content PubMed PubMed Citation Articles by Kerrigan, S. W. Articles by Leavitt, A. D. Related Collections Hemostasis, Thrombosis, and Vascular Biology Cell Adhesion and Motility Signal Transduction Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Caspase-12: a developmental link between G-protein–coupled receptors and integrin IIb3 activation Steven W. Kerrigan, Meenakshi Gaur, Ronan P. Murphy, Sanford J. Shattil, and Andrew D. Leavitt From the Department of Laboratory Medicine and Internal Medicine, University of California, San Francisco; and the Department of Cell Biology, Scripps Research Institute, La Jolla, CA. Fibrinogen binding by integrin IIb3 is promoted by platelet agonists that increase the affinity and avidity of IIb3 for fibrinogen through a process called "inside-out" signaling. Having previously demonstrated that inside-out activation of IIb3 is defective in murine megakaryocytes that lack the transcription factor NF-E2, we screened for NF-E2–regulated genes that affect IIb3 activation. Caspase-12 is the most down-regulated gene we identified in NF-E2–/– megakaryocytes. Therefore, the role of this protein in IIb3 activation was determined using platelets from caspase-12–/– mice. Despite wild-type levels of IIb3, caspase-12–/– platelets exhibit reduced fibrinogen binding to IIb3 following stimulation by adenosine diphosphate (ADP) or protease-activated receptor 4 (PAR4) receptor-activating peptide. The defect in IIb3 activation is associated with decreased cytosolic free calcium and inositol triphosphate levels, and with reduced aggregation, despite wild-type phospholipase C expression levels. In contrast, agonist-induced surface expression of P-selectin, suppression of cAMP levels following ADP stimulation, and spreading on immobilized fibrinogen are unimpaired. Moreover, although caspase-12 is highly expressed in mature megakaryocytes, it is undetectable in platelets. Taken together, these studies establish that caspase-12 expression in murine megakaryocytes is regulated, directly or indirectly, by NF-E2, and suggest that caspase-12 participates in the development of fully functional signaling pathways linking some G-protein–coupled receptors to IIb3 activation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. L. Wee and D. E. Jackson The Ig-ITIM superfamily member PECAM-1 regulates the "outside-in" signaling properties of integrin {alpha}IIb{beta}3 in platelets Blood, December 1, 2005; 106(12): 3816 - 3823. [Abstract] [Full Text] [PDF] L.-M. Lau, J. L. Wee, M. D. Wright, G. W. Moseley, P. M. Hogarth, L. K. Ashman, and D. E. Jackson The tetraspanin superfamily member CD151 regulates outside-in integrin {alpha}IIb{beta}3 signaling and platelet function Blood, October 15, 2004; 104(8): 2368 - 2375. [Abstract] [Full Text] [PDF]

	Copyright © 2004 by American Society of Hematology         Online ISSN: 1528-0020