| First Author | Bhavaraju K | Year | 2011 |
| Journal | PLoS One | Volume | 6 |
| Issue | 2 | Pages | e16586 |
| PubMed ID | 21347357 | Mgi Jnum | J:171092 |
| Mgi Id | MGI:4948420 | Doi | 10.1371/journal.pone.0016586 |
| Citation | Bhavaraju K, et al. (2011) G(12/13) signaling pathways substitute for integrin alphaIIbbeta3-signaling for thromboxane generation in platelets. PLoS One 6(2):e16586 |
| abstractText | BACKGROUND: We have previously shown that ADP-induced TXA(2) generation requires signaling from alphaIIbbeta3 integrin in platelets. Here we observed that, unlike ADP, protease-activated receptor (PAR)-mediated TXA(2) generation occurs independently of alphaIIbbeta3. 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, alphaIIbbeta3-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. |
