Aims: The collagen-stimulated generation of reactive oxygen species (ROS) regulates signal transduction in platelets, although the mechanism is unclear. The major targets of ROS include protein tyrosine phosphatases (PTPs). ROSmediated oxidation of the active cysteine site in PTPs abrogates the PTP catalytic activity. The aim of this study was to elucidate whether collagen-induced ROS generation leads to PTP oxidation, which promotes platelet stimulation. Results: SH2 domain-containing PTP-2 (SHP-2) is oxidized in platelets by ROS produced upon collagen stimulation. The oxidative inactivation of SHP-2 leads to the enhanced tyrosine phosphorylation of spleen tyrosine kinase (Syk), Vav1, and Bruton's tyrosine kinase (Btk) in the linker for the activation of T cells signaling complex, which promotes the tyrosine phosphorylation-mediated activation of phospholipase Cc2 (PLCc2). Moreover, we found that, relative to wild-type platelets, platelets derived from glutathione peroxidase 1 (GPx1)/catalase double-deficient mice showed enhanced cellular ROS levels, oxidative inactivation of SHP-2, and tyrosine phosphorylation of Syk, Vav1, Btk, and PLCc2 in response to collagen, which subsequently led to increased intracellular calcium levels, degranulation, and integrin a IIb b 3 activation. Consistent with these findings, GPx1/catalase double-deficiency accelerated the thrombotic response in FeCl 3 -injured carotid arteries. Innovation: The present study is the first to demonstrate that SHP-2 is targeted by ROS produced in collagen-stimulated platelets and suggests that a novel mechanism for the regulation of platelet activation by ROS is due to oxidative inactivation of SHP-2. Conclusion: We conclude that collagen-induced ROS production leads to SHP-2 oxidation, which promotes platelet activation by upregulating tyrosine phosphorylation-based signal transduction. Antioxid. Redox Signal. 20, 2528Signal. 20, -2540
Background: Peroxiredoxin II (PrxII) functions as a negative regulator of cellular receptor signaling by efficiently eliminating H 2 O 2 produced upon stimulation of receptors. Results: PrxII deficiency promotes GPVI-mediated platelet activation through oxidative inactivation of SH2 domain-containing tyrosine phosphatase 2. Conclusion: PrxII functions as a protective antioxidant against collagen-stimulated platelet activation and thrombosis. Significance: PrxII is a potential target in thrombovascular diseases.
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