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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 (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 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 Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted October 23, 2003 Accepted March 13, 2004 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* Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA Cell Biology, The Scripps Research Institute, La Jolla, CA, USA Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA; Internal Medicine, University of California, San Francisco, San Francisco, CA, USA * Corresponding author; email: leavitta{at}labmed2.ucsf.edu. 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 ADP or PAR4 receptor-activating peptide. This 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, while caspase-12 is highly expressed in mature wild-type megakaryocytes, it is undetectable in wild-type 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]

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