Src family kinases: at the forefront of platelet activation

Abstract

Src family kinases (SFKs) play a central role in mediating the rapid response of platelets to vascular injury. They transmit activation signals from a diverse repertoire of platelet surface receptors, including the integrin αIIbβ3, the immunoreceptor tyrosine–based activation motif–containing collagen receptor complex GPVI-FcR γ-chain, and the von Willebrand factor receptor complex GPIb-IX-V, which are essential for thrombus growth and stability. Ligand-mediated clustering of these receptors triggers an increase in SFK activity and downstream tyrosine phosphorylation of enzymes, adaptors, and cytoskeletal proteins that collectively propagate the signal and coordinate platelet activation. A growing body of evidence has established that SFKs also contribute to Gq- and Gi-coupled receptor signaling that synergizes with primary activation signals to maximally activate platelets and render them prothrombotic. Interestingly, SFKs concomitantly activate inhibitory pathways that limit platelet activation and thrombus size. In this review, we discuss past discoveries that laid the foundation for this fundamental area of platelet signal transduction, recent progress in our understanding of the distinct and overlapping functions of SFKs in platelets, and new avenues of research into mechanisms of SFK regulation. We also highlight the thrombotic and hemostatic consequences of targeting platelet SFKs.

Modulation and pre-amplification of PAR1 signaling by ADP acting via the P2Y12 receptor during platelet subpopulation formation

“…It was shown that Gαi-receptors can activate such SFK as Lyn [55], which results in PLCγ and PI3K activation [6,56,57]. Furthermore, SFK inhibitors can abolish platelet aggregation [55].…”

Integrin αIIbβ3 outside-in signaling

“…55 Further work using mouse platelets singly or doubly deficient in SFKs has revealed both unique and overlapping roles for individual family members, with c-Src and Lyn proving to be the dominant effectors of a IIb b 3 outside-in driven responses, although Lyn appears to hold both positive and negative roles. 11,56,57 Although cSrc, Lyn, and Fyn are the more highly expressed SFKs in platelets, 56,[58][59][60] differences in the relative abundance of these kinases between mouse and human platelets mean an element of caution should be applied when interpreting mouse platelets as a model for human platelet SFK signaling; historical SFK inhibitors are also likely to have off-target effects.…”

Platelet–neutrophil interactions under thromboinflammatory conditions

“…It is known that there are 7–8 members of SFKs in human platelets and neutrophils [110, 111]. Inhibition of SFKs with PP2, a broad-spectrum SFK inhibitor, partially impaired thrombin-mediated P-selectin exposure and αIIbβ3 integrin activation [112].…”