Platelet Src family kinases: A tale of reversible phosphorylation

Sarcoma (Src) family kinases (SFKs) have occupied a central place in platelet research for over 40 years. Discovered by virologists and oncologists as the proto proto‐oncogene, Src tyrosine kinase spurred a phenomenal burst of research on reversible tyrosine phosphorylation and signal transduction. For a time, platelets were adopted as the model of choice for studying the biological functions of Src, owing to their ease of isolation, high Src expression, and lack of a nucleus, only to be abandoned due to challenges of culturing and manipulating using common molecular biology‐based techniques. For platelet biologists, SFKs have remained an important area of investigation, initiating and amplifying signals from all major adhesion, activation, and inhibitory receptors, including the integrin αIIbβ3, the collagen receptor complex glycoprotein VI–Fc receptor γ‐chain, the G protein–coupled ADP receptor P2Y(12) and the inhibitory receptors platelet endothelial cell adhesion molecule‐1 and G6b‐B. The vital roles of SFKs in platelets is highlighted by the severe phenotypes of null and gain‐of‐function mutations in SFKs in mice and humans, and effects of pharmacologic inhibitors on platelet activation, thrombosis, and hemostasis. The recent description of critical regulators of SFKs in platelets, namely, C‐terminal Src kinase (Csk), Csk homologous kinase (Chk), the receptor‐type protein‐tyrosine phosphatase receptor type J (PTPRJ) helps explain some of the bleeding side effects of tyrosine kinase inhibitors and are novel therapeutic targets for regulating the thrombotic and hemostatic capacity of platelets. Recent findings from Chk, Csk, and PTPRJ knockout mouse models highlighted that SFKs are able to autoinhibit by phosphorylating their C‐terminal tyrosine residues, providing fundamental insights into SFK autoregulation.