Tucker Katherine L, Sage Tanya, Stevens Joanne M, Jordan Peter A, Jones Sarah, Barrett Natasha E, St-Arnaud Rene, Frampton Jonathan, Dedhar Shoukat, Gibbins Jonathan M
Institute of Cardiovascular and Metabolic Research and School of Biological Sciences, University of Reading, Reading, United Kingdom.
Blood. 2008 Dec 1;112(12):4523-31. doi: 10.1182/blood-2008-03-148502. Epub 2008 Sep 4.
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 beta1- and beta3-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 PLCgamma2 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.
整合素连接激酶（ILK）参与调控一系列基本生物学过程，如细胞存活、生长、分化和黏附。在血小板中，ILK与含β1和β3的整合素相关联，这对血小板的功能至关重要。血小板受到刺激后，这种与整合素的关联增强，ILK激酶活性上调，提示ILK可能对血小板反应的协调起重要作用。在本研究中，构建了条件性基因敲除小鼠模型以研究ILK在血小板中的作用。ILK缺陷小鼠的出血时间和出血量增加，尽管超微结构正常，但ILK缺陷血小板的功能显著降低。这包括在动脉血流条件下聚集减少、纤维蛋白原结合减少和血栓形成减少。此外，尽管早期胶原刺激的信号，如PLCγ2磷酸化和钙动员在ILK缺陷血小板中未受影响，但观察到α颗粒而非致密颗粒分泌存在选择性缺陷。这些结果表明，除了参与整合素亲和力的控制外，ILK对α颗粒分泌是必需的，因此可能在血小板功能调节中起核心作用。
