Sather Susan, Kenyon Karla D, Lefkowitz Jerry B, Liang Xiayuan, Varnum Brian C, Henson Peter M, Graham Douglas K
Department of Pediatrics, University of Colorado at Denver, and Health Sciences Center, Aurora, CO 80045, USA.
Blood. 2007 Feb 1;109(3):1026-33. doi: 10.1182/blood-2006-05-021634. Epub 2006 Oct 17.
Membrane-bound receptors generate soluble ligand-binding domains either by proteolytic cleavage of the extracellular domain or alternative mRNA splicing yielding a secreted protein. Mertk (Mer) is in a receptor tyrosine kinase family with Axl and Tyro-3, and all 3 receptors share the Gas6 ligand. Mer regulates macrophage activation, promotes apoptotic cell engulfment, and supports platelet aggregation and clot stability in vivo. We have found that the membrane-bound Mer protein is cleaved in the extracellular domain via a metalloproteinase. The cleavage results in the production of a soluble Mer protein released in a constitutive manner from cultured cells. Significant amounts of the soluble Mer protein were also detected in human plasma, suggesting its physiologic relevance. Cleavage of Mer was enhanced by treatment with LPS and PMA and was specifically inhibited by a tumor necrosis factor alpha-converting enzyme metalloproteinase inhibitor. As a decoy receptor for Gas6, soluble Mer prevented Gas6-mediated stimulation of membrane-bound Mer. The inhibition of Gas6 activity by soluble Mer led to defective macrophage-mediated engulfment of apoptotic cells. Furthermore, soluble Mer decreased platelet aggregation in vitro and prevented fatal collagen/epinephrine-induced thromboembolism in mice, suggesting a potential therapeutic use for soluble Mer in the treatment of clotting disorders.
膜结合受体通过细胞外结构域的蛋白水解切割或产生分泌蛋白的可变mRNA剪接来生成可溶性配体结合结构域。Mertk（Mer）属于与Axl和Tyro-3同属的受体酪氨酸激酶家族，并且所有这三种受体都共享Gas6配体。Mer调节巨噬细胞活化，促进凋亡细胞吞噬，并在体内支持血小板聚集和血凝块稳定性。我们发现膜结合的Mer蛋白在细胞外结构域通过金属蛋白酶进行切割。这种切割导致产生一种可溶性Mer蛋白，该蛋白以组成性方式从培养细胞中释放出来。在人血浆中也检测到大量的可溶性Mer蛋白，表明其具有生理相关性。用LPS和PMA处理可增强Mer的切割，并且可被肿瘤坏死因子α转换酶金属蛋白酶抑制剂特异性抑制。作为Gas6的诱饵受体，可溶性Mer可防止Gas6介导的对膜结合Mer的刺激。可溶性Mer对Gas6活性的抑制导致巨噬细胞介导的凋亡细胞吞噬缺陷。此外，可溶性Mer在体外降低血小板聚集，并防止小鼠发生致命的胶原/肾上腺素诱导的血栓栓塞，这表明可溶性Mer在治疗凝血障碍方面具有潜在的治疗用途。
