iMer, a naturally occurring MERTK splice variant, binds to GAS6 to decrease platelet activation and thrombus formation

Blood Vessels, Thrombosis & Hemostasis Pub Date : 2025-08-01 DOI:10.1016/j.bvth.2025.100078

Stephanie Springborn , Samantha Judd , Patricia Morateck , David VanderZee , Adam Kidwell , Christine Brzezinski , Allaura Cox , Susan Sather , Keith B. Neeves , Deborah DeRyckere , Jorge Di Paola , Douglas K. Graham , Brian R. Branchford

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Abstract

Unopposed platelet activation can be associated with pathologic thrombosis. An intact growth arrest–specific gene 6 (GAS6)/Mer receptor tyrosine kinase (MERTK) signaling pathway contributes importantly to potentiating platelet activation triggered by molecular agonists ex vivo and thrombus stabilization in vivo. We describe, herein, the inhibition of platelet function and stable thrombus formation conferred by iMer, a naturally occurring MERTK splice variant, that acts as a GAS6 decoy receptor and decreases phosphorylation of MERTK. Human and murine platelets incubated with this truncated protein demonstrate reduced activation in ex vivo assays including aggregometry (similar to treatment with anti-GAS6 antibody), expression of P-selectin, spreading on collagen, and accumulation on collagen at a venous shear rate. Wild-type C57BL/6 mice treated with iMer had improved survival in a collagen/epinephrine-induced pulmonary embolism model, without increase in tail bleeding time on preliminary analysis. Taken together, these findings confirm previous data suggesting the importance of GAS6-MERTK signaling in platelet activation and thrombus formation and highlighting the potential therapeutic implications of targeting this pathway as a means of treating or preventing thrombosis.

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iMer是一种天然存在的MERTK剪接变体，与GAS6结合以减少血小板活化和血栓形成

抗血小板活化可能与病理性血栓形成有关。完整的生长抑制特异性基因6 (GAS6)/Mer受体酪氨酸激酶（MERTK）信号通路对增强分子激动剂触发的血小板活化和体内血栓稳定起重要作用。本文中，我们描述了一种天然存在的MERTK剪接变体iMer对血小板功能的抑制和稳定血栓形成的作用，它作为GAS6诱饵受体并降低MERTK的磷酸化。用这种截断的蛋白孵育的人和小鼠血小板在体外实验中显示出活性降低，包括聚集（类似于用抗gas6抗体处理）、p -选择素的表达、在胶原上的扩散和在胶原上的静脉剪切速率积累。在胶原/肾上腺素诱导的肺栓塞模型中，经iMer处理的野生型C57BL/6小鼠存活率提高，初步分析显示尾出血时间未增加。综上所述，这些发现证实了先前的数据，表明GAS6-MERTK信号在血小板激活和血栓形成中的重要性，并强调了靶向该途径作为治疗或预防血栓形成的手段的潜在治疗意义。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Blood Vessels, Thrombosis & Hemostasis

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