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Blood, 1 December 2008, Vol. 112, No. 12, pp. 4523-4531.
Prepublished online as a Blood First Edition Paper on September 4, 2008; DOI 10.1182/blood-2008-03-148502.


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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY

A dual role for integrin-linked kinase in platelets: regulating integrin function and {alpha}-granule secretion

Katherine L. Tucker1, Tanya Sage1, Joanne M. Stevens1, Peter A. Jordan1, Sarah Jones1, Natasha E. Barrett1, Rene St-Arnaud2, Jonathan Frampton3, Shoukat Dedhar4, and Jonathan M. Gibbins1

1 Institute of Cardiovascular and Metabolic Research and School of Biological Sciences, University of Reading, Reading, United Kingdom; 2 Departments of Surgery and Human Genetics, McGill University, Montréal, QC; 3 Division of Immunity and Infection, Birmingham University Medical School, Edgbaston, United Kingdom; and 4 The BC Cancer Research Centre, Vancouver, BC

Integrin-linked kinase (ILK) has been implicated in the regulation of a range of fundamental biological processes such as cell survival, growth, differentiation, and adhesion. In platelets ILK associates with β1- and β3-containing integrins, which are of paramount importance for the function of platelets. Upon stimulation of platelets this association with the integrins is increased and ILK kinase activity is up-regulated, suggesting that ILK may be important for the coordination of platelet responses. In this study a conditional knockout mouse model was developed to examine the role of ILK in platelets. The ILK-deficient mice showed an increased bleeding time and volume, and despite normal ultrastructure the function of ILK-deficient platelets was decreased significantly. This included reduced aggregation, fibrinogen binding, and thrombus formation under arterial flow conditions. Furthermore, although early collagen stimulated signaling such as PLC{gamma}2 phosphorylation and calcium mobilization were unaffected in ILK-deficient platelets, a selective defect in {alpha}-granule, but not dense-granule, secretion was observed. These results indicate that as well as involvement in the control of integrin affinity, ILK is required for {alpha}-granule secretion and therefore may play a central role in the regulation of platelet function.


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