Distinct pathways regulate Syk activation downstream of ITAM and hemITAM receptors in platelets [Cell Biology]
March 12th, 2015 by Manne, B. K., Badolia, R., Dangelmaier, C., Eble, J. A., Ellmeier, W., Kahn, M., Kunapuli, S. P.
Tyrosine kinase pathways are known to play an important role in the activation of platelets. In particular, the GPVI and CLEC-2 receptors are known to activate Syk upon tyrosine phosphorylation of an Immune Tyrosine Activation Motif (ITAM) and hemi-ITAM, respectively. However, unlike GPVI, the CLEC-2 receptor contains only one tyrosine motif in the intracellular domain. The mechanisms by which this receptor activates Syk are not completely understood. In this study, we identified a novel signaling mechanism in CLEC-2-mediated Syk activation. CLEC-2-mediated, but not GPVI-mediated, platelet activation and Syk phosphorylation were abolished by inhibition of PI3-Kinase, which demonstrates that PI3-Kinase regulates Syk downstream of CLEC-2. Ibrutinib, a Tec family kinase inhibitor, also completely abolished CLEC-2-mediated aggregation and Syk phosphorylation in human and murine platelets. Furthermore, Embryos lacking both Btk-/- and Tec-/- exhibited cutaneous edema associated with blood-filled vessels in a typical lymphatic pattern similar to CLEC-2 or Syk-deficient embryos. Thus our data show, for the first time, that PI3-Kinase and Tec family kinases play a crucial role in the regulation of platelet activation and Syk phosphorylation downstream of the CLEC-2 receptor.