Distinct Role of Pyk2 in Mediating Thromboxane Generation Downstream of Both G(12/13) and Integrin alpha IIb beta 3 in Platelets

作者：Kim Soochong; Cipolla Lina; Guidetti Gianni; Okigaki Mitsuhiko; Jin Jianguo; Torti Mauro; Kunapuli Satya P^*

来源：Journal of Biological Chemistry, 2013, 288(25): 18194-18203.

DOI：10.1074/jbc.M113.461087

Proline-rich tyrosine kinase 2 (Pyk2) is activated by various agonists in platelets. We evaluated the signaling mechanism and the functional role of Pyk2 in platelets by using pharmacological inhibitors and Pyk2-deficient platelets. We found that platelet aggregation and secretion in response to 2-methylthio-ADP (2-MeSADP) and AYPGKF were diminished in the presence of Pyk2 inhibitors or in Pyk2-deficient platelets, suggesting that Pyk2 plays a positive regulatory role in platelet functional responses. It has been shown that ADP-, but not thrombin-induced thromboxane (TxA(2)) generation depends on integrin signaling. Unlike ADP, thrombin activates G(12/13) pathways, and G(12/13) pathways can substitute for integrin signaling for TxA(2) generation. We found that Pyk2 was activated downstream of both G(12/13) and integrin-mediated pathways, and both 2-Me-SADP- and AYPGKF-induced TxA(2) generation was significantly diminished in Pyk2-deficient platelets. In addition, TxA(2) generation induced by co-stimulation of G(i) and G(z) pathways, which is dependent on integrin signaling, was inhibited by blocking Pyk2. Furthermore, inhibition of 2-MeSADP-induced TxA(2) generation by fibrinogen receptor antagonist was not rescued by co-stimulation of G(12/13) pathways in the presence of Pyk2 inhibitor. We conclude that Pyk2 is a common signaling effector downstream of both G(12/13) and integrin alpha IIb beta 3 signaling, which contributes to thromboxane generation.

• 出版日期2013-6-21