The (Patho)Biology of SRC Kinase in Platelets and Megakaryocytes

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.

Integrin αIIbβ3 outside-in signaling activates human platelets through serine 24 phosphorylation of Disabled-2

“…Integrin αIIbβ3 outside-in signaling activates Src and PKC signaling causing granule secretion, TXA2 synthesis and platelet spreading [ 39 , 42 ]. PLD1 is also involved in outside-in signaling of integrin αIIbβ3 by supporting platelet adhesion, spreading and plug formation, thus stabilizing thrombus formation [ 43 ].…”

“…Integrin αIIbβ3 outside-in signaling activates Src and PKC signaling causing granule secretion, TXA2 synthesis and platelet spreading [39,42]. PLD1 is also involved .…”

The mechanism of Lingze tablets in the treatment of benign prostatic hyperplasia based on network pharmacology and molecular docking technology

“…In normal tissues, Src kinases are signal transduction centres that coordinate cellular responses to extracellular stimuli. Src is the ligand of epidermal growth factor receptor, platelet‐derived growth factor receptor, fibroblast growth factor receptor and other growth factor receptors, which can promote the movement, proliferation, invasion and metastasis of tumour cells, and play an important role in tumour genesis and development (De Kock & Freson, 2020). Wang et al suggests a dual role of SRC in smooth muscle of the hyperplastic human prostate, which appears to regulate prostate smooth muscle tone by promoting contraction, and may be critical for prostate growth, by triggering proliferation in the stroma (Wang et al, 2016).…”

Pathogenic Aspects of Inherited Platelet Disorders

“…αIIbβ3-mediated “outside-in” signaling is initiated by activation of Src. 60 Patients with a “gain of function” variant in the SRC gene present with thrombocytopenia, myelofibrosis, severe bleeding diathesis, and bone defects. 61 In patients with Src defect, the number of α-granules in platelets is reduced.…”