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Background  We have previously shown that ADP-induced TXA 2  generation requires signaling from αIIbβ3 integrin in platelets. Here we observed that, unlike ADP, protease-activated receptor (PAR)-mediated TXA 2  generation occurs independently of αIIbβ3. PAR agonists, but not ADP, activate G 12/13  signaling pathways. Hence, we evaluated the role of these pathways in TXA 2  generation.    Principal Findings  Inhibition of ADP-induced thromboxane generation by fibrinogen receptor antagonist SC57101 was rescued by co-stimulation of G 12/13  pathways with YFLLRNP. This observation suggested an existence of a common signaling effector downstream of integrins and G 12/13  pathways. Hence, we evaluated role of three potential tyrosine kinases; c-Src, Syk and FAK (Focal Adhesion Kinase) that are known to be activated by integrins. c-Src and Syk kinase did not play a role in ADP-induced functional responses in platelets. Selective activation of G 12/13  pathways resulted in the activation of FAK, in the absence of integrin signaling. Interestingly, αIIbβ3-mediated FAK activation occurred in a Src family kinase (SFK)-independent manner whereas G 12/13  pathway caused FAK activation in a SFK and RhoA-dependent manner. A FAK selective inhibitor TAE-226, blocked TXA 2  generation. However, in comparison to WT mice, Pf4-Cre/Fak-Floxed mice did not show any difference in platelet TXA 2  generation.    Conclusions  Therefore, we conclude that differential activation of FAK occurs downstream of Integrins and G 12/13  pathways. However, the common effector molecule, possibly a tyrosine kinase downstream of integrins and G 12/13  pathways contributing to TXA 2  generation in platelets remains elusive.

G12/13 Signaling Pathways Substitute for Integrin αIIbβ3-Signaling for Thromboxane Generation in Platelets