CalDAG-GEFI and platelet activation
The regulated activation of platelets is an essential component of thrombosis and hemostasis. Platelet stimulation through G protein-coupled and immunoglobulin-like receptors leads to the activation of phospholipase C (PLC) beta 2/3 and PLC gamma 2, respectively, which in turn mediate the generation of the second messengers calcium (Ca(2+)) and diacylgy-cerol (DAG). DAG is critical for protein kinase C (PKC) activation, a key event in platelet granule release and integrin activation . Ca(2+) triggers many intracellular signaling processes important for various platelet responses such as integrin activation and the generation of autocrine agonists, such as ADP and TxA(2). In our recent work, we identified the guanine nucleotide exchange factor, CalDAG-GEFI, as a critical molecule in Ca(2+) signaling in platelets [2-5]. CalDAG-GEFI activates the small GTPase Rap1, a central molecular switch that drives platelet activation by directly regulating integrin-mediated aggregation [2-4, 6] and the release of autocrine agonists . Here, we review key findings that highlight how one molecule, CalDAG-GEFI, coordinates various Ca(2+)-dependent platelet responses ensuring the rapid activation of platelets at the site of vascular injury.