Targeted downregulation of platelet CLEC-2 occurs through Syk-independent internalization.

Blood
Viola LorenzBernhard Nieswandt

Abstract

Platelet aggregation at sites of vascular injury is not only essential for hemostasis, but may also cause acute ischemic disease states such as myocardial infarction or stroke. The hemi-immunoreceptor tyrosine-based activation motif-containing C-type lectinlike receptor 2 (CLEC-2) mediates powerful platelet activation through a Src- and spleen tyrosine kinase (Syk)-dependent tyrosine phosphorylation cascade. Thereby, CLEC-2 not only contributes to thrombus formation and stabilization but also plays a central role in blood-lymphatic vessel development, tumor metastasis, and prevention of inflammatory bleeding, making it a potential pharmacologic target to modulate these processes. We have previously shown that injection of the anti-CLEC-2 antibody, INU1, results in virtually complete immunodepletion of platelet CLEC-2 in mice, which is, however, preceded by a severe transient thrombocytopenia thereby limiting its potential therapeutic use. The mechanisms underlying this targeted CLEC-2 downregulation have remained elusive. Here, we show that INU1-induced CLEC-2 immunodepletion occurs through Src-family kinase-dependent receptor internalization in vitro and in vivo, presumably followed by intracellular degradation. In mice with p...Continue Reading

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Citations

Jun 24, 2016·Platelets·Markus BenderBernhard Nieswandt
Jun 5, 2018·Platelets·Katsue Suzuki-Inoue
Jun 27, 2017·Current Opinion in Hematology·Meenakshi Banerjee, Sidney W Whiteheart
Aug 25, 2017·Blood·Elizabeth J HainingBernhard Nieswandt
Jun 27, 2015·Blood·Debra K Newman
Mar 5, 2020·Platelets·Elizabeth J HainingSteve P Watson
Jun 20, 2020·Platelets·Phillip Lr NicolsonSteve P Watson
Apr 20, 2018·Nature Communications·Joachim PircherChristian Schulz
Oct 12, 2018·Journal of Hematology & Oncology·Martin Schlesinger
Sep 16, 2020·Proceedings of the National Academy of Sciences of the United States of America·Shuchi GuptaLawrence F Brass
Dec 29, 2016·Journal of Thrombosis and Haemostasis : JTH·T ShiraiK Suzuki-Inoue
Jan 3, 2019·The Journal of Clinical Investigation·Julie RayesBernhard Nieswandt
Aug 28, 2020·Frontiers in Cellular Neuroscience·Agnieszka M JurgaKatarzyna Z Kuter
Aug 18, 2021·Journal of Thrombosis and Haemostasis : JTH·Surasak WichaiyoNoppawan Phumala Morales

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