Platelets are subcellular particles produced by megakaryocytes that circulate in blood. As discs, they patrol the blood-endothelial interface, and in response to vascular damage, rapidly change shape, in a reaction driven by robust actin filament assembly and cytoskeletal reorganization. Activation converts them into spread forms that can plug vascular leaks and recruit additional platelets to form a patch. Filamin A (FLNa), first identified by us in 1976, is a multifaceted protein abundantly expressed in platelets where it is known to crosslink actin filaments and link them to the GP1b chain of the von Willebrand factor receptor. Humans and mice lacking FLNa have severe developmental abnormalities, accompanied by stroke and hemorrhage. The generation of platelets that lack filamin A (FLNa) in mice and the initial characterization of the many defects identifiable in these platelets, have revealed an intimate relationship between platelet FLNa and ITAM-based receptor signaling. In the aims, we will determine how a direct interaction of FLNa with Syk promotes signaling from platelet ITAM-based receptors.
Aim 1 will delineate the binding interface between FLNa and Syk.
Aim 2 will determine how FLNa modulates Syk function in cells.
Aim 3 will establish the physiological importance of this interaction.
Dissection of the FLNa-Syk signal transduction pathway will provide both new insight into the mechanisms of platelet activation and aggregation, and lead to the development of new antithrombotic drugs to aid in the prevention of vascular ischemic events (myocardial infarction, stroke, vascular death) in patients with a history of symptomatic atherosclerotic disease. Pharmacological relief of the FLNa-Syk interaction may diminish platelet responses and prove clinically beneficial.
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