Abstract
Proto-oncogene tyrosine-protein kinase SRC (SRC), as other members of the SRC family kinases (SFK), plays an important role in regulating signal transduction by different cell surface receptors after changes in the cellular environment. Here, we reviewed the role of SRC in platelets and megakaryocytes (MK). In platelets, inactive closed SRC is coupled to the β subunit of integrin αIIbβ3 while upon fibrinogen binding during platelet activation, αIIbβ3-mediated outside-in signaling is initiated by activation of SRC. Active open SRC now further stimulates many downstream effectors via tyrosine phosphorylation of enzymes, adaptors, and especially cytoskeletal components. Functional platelet studies using SRC knockout mice or broad spectrum SFK inhibitors pointed out that SRC mediates their spreading on fibrinogen. On the other hand, an activating pathological SRC missense variant E527K in humans that causes bleeding inhibits collagen-induced platelet activation while stimulating platelet spreading. The role of SRC in megakaryopoiesis is much less studied. SRC knockout mice have a normal platelet count though studies with SFK inhibitors point out that SRC could interfere with MK polyploidization and proplatelet formation but these inhibitors are not specific. Patients with the SRC E527K variant have thrombocytopenia due to hyperactive SRC that inhibits proplatelet formation after increased spreading of MK on fibrinogen and enhanced formation of podosomes. Studies in humans have contributed significantly to our understanding of SRC signaling in platelets and MK.
Highlights
Introduction to SRC and SRC FamilyKinasesOver 100 years ago, the discovery of Rous sarcoma virus causing tumor growth in chickens, led to the characterization of the viral v-SRC gene [1]
In vivo administration of Dasatinib, a broad spectrum tyrosine kinase inhibitors (TKI), in mice causes a 30% reduction in platelet count, which is similar to the mild thrombocytopenia present in chronic myeloid leukemia (CML) patients treated with Dasatinib [53]
The role of SRC in platelet biology has been extensively studied and reveals its important role in integrin αIIb β3 outside-in signaling upon fibrinogen binding
Summary
Over 100 years ago, the discovery of Rous sarcoma virus causing tumor growth in chickens, led to the characterization of the viral v-SRC gene [1] This was followed by the discovery that v-SRC is a tyrosine kinase protein, essential for cell transformation by the Rous sarcoma virus, and derived from cellular chicken c-SRC, incorporated into Rous sarcoma virus via recombination [2]. Intramolecular binding of phosphorylated Y530 to the SH2 SRC domain results in blocking of the catalytic site necessary for kinase activation and keeps SRC in a closed inactive state under normal cellular conditions [6,7] (Figure 1A). Pathogenic somatic SRC variants disturbing the SH2–Y530 interaction result in continuous SRC activation as found in colon and endometrial cancer [9,10]. Y530, such as the germline E527K variant, disturb the SH2–Y530 interaction and result in domains allowscontinuous (auto)phosphorylation of Y419 and activation of SRC. Such as the germline E527K variant, disturb the SH2–Y530 interaction and result in continuous
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