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Blood. 2004 Sep 1;104(5):1327-34. Epub 2004 Apr 1.

Caspase-12: a developmental link between G-protein-coupled receptors and integrin alphaIIbbeta3 activation.

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Department of Laboratory Medicine, University of California-San Francisco, 513 Parnassus Ave, Rm S-577, San Francisco, CA 94143-0100, USA.


Fibrinogen binding by integrin alphaIIbbeta3 is promoted by platelet agonists that increase the affinity and avidity of alphaIIbbeta3 for fibrinogen through a process called "inside-out" signaling. Having previously demonstrated that inside-out activation of alphaIIbbeta3 is defective in murine megakaryocytes that lack the transcription factor NF-E2, we screened for NF-E2-regulated genes that affect alphaIIbbeta3 activation. Caspase-12 is the most down-regulated gene we identified in NF-E2(-/-) megakaryocytes. Therefore, the role of this protein in alphaIIbbeta3 activation was determined using platelets from caspase-12(-/-) mice. Despite wild-type levels of alphaIIbbeta3, caspase-12(-/-) platelets exhibit reduced fibrinogen binding to alphaIIbbeta3 following stimulation by adenosine diphosphate (ADP) or protease-activated receptor 4 (PAR4) receptor-activating peptide. The defect in alphaIIbbeta3 activation is associated with decreased cytosolic free calcium and inositol triphosphate levels, and with reduced aggregation, despite wild-type phospholipase Cbeta 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 alphaIIbbeta3 activation.

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