The Tyrosine Kinase c-Src Specifically Binds to the Active Integrin αIIbβ3 to Initiate Outside-in Signaling in Platelets

Wu, Yibing; Span, Lisa M.; Nygren, Patrik; Zhu, Hua; Moore, David T.; Cheng, Hong; Röder, Heinrich; DeGrado, Willliam F.; Bennett, Joel S.

doi:10.1074/jbc.m115.648428

Cited by 28 publications

(21 citation statements)

References 34 publications

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“…41 In addition to this, Src family kinases (SFKs), specifically c-Src, have been shown to be crucial for integrin outside-in signaling, and quercetin potently inhibits SFKs including Fyn and Lyn. 35 42 An inhibition of platelet activation induced by thrombin here agrees with the GPCR-stimulated aggregometry presented in this study, and offers further evidence for quercetin and its metabolites as inhibitors of the thrombin-stimulated platelet activation pathway, even in the presence of plasma proteins. Quercetin has also exhibited anticoagulant activities in numerous studies, including inhibitory effects on the enzymatic activity of thrombin and Factor Xa.…”

Section: Discussionsupporting

confidence: 87%

The Metabolites of the Dietary Flavonoid Quercetin Possess Potent Antithrombotic Activity, and Interact with Aspirin to Enhance Antiplatelet Effects

Stainer

Sasikumar

Bye

et al. 2019

TH Open

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Quercetin, a dietary flavonoid, has been reported to possess antiplatelet activity. However, its extensive metabolism following ingestion has resulted in difficulty elucidating precise mechanisms of action. In this study, we aimed to characterize the antiplatelet mechanisms of two methylated metabolites of quercetin—isorhamnetin and tamarixetin—and explore potential interactions with aspirin. Isorhamnetin and tamarixetin inhibited human platelet aggregation, and suppressed activatory processes including granule secretion, integrin αIIbβ3 function, calcium mobilization, and spleen tyrosine kinase (Syk)/linker for activation of T cells (LAT) phosphorylation downstream of glycoprotein VI with similar potency to quercetin. All three flavonoids attenuated thrombus formation in an in vitro microfluidic model, and isoquercetin, a 3-O-glucoside of quercetin, inhibited thrombosis in a murine laser injury model. Isorhamnetin, tamarixetin, and quercetin enhanced the antiplatelet effects of aspirin more-than-additively in a plate-based aggregometry assay, reducing aspirin IC50 values by an order of magnitude, with this synergy maintained in a whole blood test of platelet function. Our data provide mechanistic evidence for the antiplatelet activity of two quercetin metabolites, isorhamnetin and tamarixetin, and suggest a potential antithrombotic role for these flavonoids. In combination with their interactions with aspirin, this may represent a novel avenue of investigation for the development of new antithrombotic strategies and management of current therapies.

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Section: Discussionsupporting

confidence: 87%

The Metabolites of the Dietary Flavonoid Quercetin Possess Potent Antithrombotic Activity, and Interact with Aspirin to Enhance Antiplatelet Effects

Stainer

Sasikumar

Bye

et al. 2019

TH Open

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“…22,55,61 More recent work demonstrates, however, that c-Src associates with b 3 predominantly after platelet activation. 62 Furthermore, an interaction of Ga 13 with an ExE motif in the b 3 -integrin tail has been demonstrated as a key early event required for the activation of c-Src to initiate outside-in signaling, a process Reduced tail-bleeding time.…”

Section: Src-family Kinasesmentioning

confidence: 99%

Integrin αIIbβ3 outside-in signaling

Durrant

Bosch

Hers

2017

Blood

192

175

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Integrin αIIbβ3 is a highly abundant heterodimeric platelet receptor that can transmit information bidirectionally across the plasma membrane, and plays a critical role in hemostasis and thrombosis. Upon platelet activation, inside-out signaling pathways increase the affinity of αIIbβ3 for fibrinogen and other ligands. Ligand binding and integrin clustering subsequently stimulate outside-in signaling, which initiates and amplifies a range of cellular events driving essential platelet processes such as spreading, thrombus consolidation, and clot retraction. Integrin αIIbβ3 has served as an excellent model for the study of integrin biology, and it has become clear that integrin outside-in signaling is highly complex and involves a vast array of enzymes, signaling adaptors, and cytoskeletal components. In this review, we provide a concise but comprehensive overview of αIIbβ3 outside-in signaling, focusing on the key players involved, and how they cooperate to orchestrate this critical aspect of platelet biology. We also discuss gaps in the current understanding of αIIbβ3 outside-in signaling and highlight avenues for future investigation.

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“…The kinase of Src family is well-known to be the downstream target of integrin, in which Src is a key member 29 . Previous study revealed that Src is able to activate Erk, a kinase that can phosphorylate p47 phox and then induce its membrane translocation 30 , 31 .…”

Section: Resultsmentioning

confidence: 99%

2,5-Hexanedione induces dopaminergic neurodegeneration through integrin αMβ2/NADPH oxidase axis-mediated microglial activation

et al. 2018

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Recent study demonstrated that chronic exposure to solvents increases the risk of Parkinson’s disease (PD), the second most common neurodegenerative disorder characterized by progressive dopaminergic neurodegeneration in the substantia nigra (SN). n-Hexane, a widely used organic solvent, displays central-peripheral neurotoxicity, which is mainly mediated by its active metabolite, 2,5-hexanedione (HD). However, whether HD exposure contributes to PD remains unclear. In this study, we found that rats exposed to HD displayed progressive dopaminergic neurodegeneration in the nigrostriatal system. Microglial activation was also detected in HD-treated rats, which occurred prior to degeneration of dopaminergic neurons. Moreover, depletion of microglia markedly reduced HD-induced dopaminergic neurotoxicity. Mechanistic study revealed an essential role of microglial integrin αMβ2-NADPH oxidase (NOX2) axis in HD-elicited neurotoxicity. HD activated NOX2 by inducing membrane translocation of NOX2 cytosolic subunit, p47phox. Integrin αMβ2 was critical for HD-induced NOX2 activation since inhibition or genetic deletion of αMβ2 attenuated NOX2-generated superoxide and p47phox membrane translocation in response to HD. Src and Erk, two downstream signals of αMβ2, were recognized to bridge HD/αMβ2-mediated NOX2 activation. Finally, pharmacological inhibition of αMβ2-NOX2 axis attenuated HD-induced microglial activation and dopaminergic neurodegeneration. Our findings revealed that HD exposure damaged nigrostriatal dopaminergic system through αMβ2-NOX2 axis-mediated microglial activation, providing, for the first time, experimental evidence for n-hexane exposure contributing to the etiology of PD.

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The Tyrosine Kinase c-Src Specifically Binds to the Active Integrin αIIbβ3 to Initiate Outside-in Signaling in Platelets

Cited by 28 publications

References 34 publications

The Metabolites of the Dietary Flavonoid Quercetin Possess Potent Antithrombotic Activity, and Interact with Aspirin to Enhance Antiplatelet Effects

The Metabolites of the Dietary Flavonoid Quercetin Possess Potent Antithrombotic Activity, and Interact with Aspirin to Enhance Antiplatelet Effects

Integrin αIIbβ3 outside-in signaling

2,5-Hexanedione induces dopaminergic neurodegeneration through integrin αMβ2/NADPH oxidase axis-mediated microglial activation

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