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首页> 外文期刊>Translational research: the journal of laboratory and clinical medicine >M10, a caspase cleavage product of the hepatocyte growth factor receptor, interacts with Smad2 and demonstrates antifibrotic properties in vitro and in vivo
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M10, a caspase cleavage product of the hepatocyte growth factor receptor, interacts with Smad2 and demonstrates antifibrotic properties in vitro and in vivo

机译：M10是肝细胞生长因子受体的半胱天冬酶裂解产物，与Smad2相互作用并在体外和体内显示抗纤维化特性

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Hepatocyte growth factor receptor, also known as cellular mesenchymal-epithelial transition factor (c-MET, MET), is an important antifibrotic molecule that protects various tissues, including lung, from injury and fibrosis. The intracellular cytoplasmic tail of MET contains a caspase-3 recognition motif "DEVD-T" that on cleavage by caspase-3 generates a 10-amino acid peptide, TRPASFWETS, designated as "M10". M10 contains at its N-terminus the uncharged amino acid proline (P) directly after a cationic amino acid arginine (R) which favors the transport of the peptide through membranes. M10, when added to cell culture medium, remains in the cytoplasm and nuclei of cells for up to 24 hours. M10 effectively decreases collagen in both scleroderma and TGF beta-stimulated normal lung and skin fibroblasts. M10 interacts with the Mad Homology 2 domain of Smad2 and inhibits TGF beta-induced Smad2 phosphorylation, suggesting that the antifibrotic effects of M10 are mediated in part by counteracting Smad-dependent fibrogenic pathways. In the bleomycin murine model of pulmonary fibrosis, M10 noticeably reduced lung inflammation and fibrosis. Ashcroft fibrosis scores and lung collagen content were significantly lower in bleomycin-treated mice receiving M10 as compared with bleomycin-treated mice receiving scrambled peptide. We conclude that M10 peptide interacts with Smad2 and demonstrates strong antifibrotic effects in vitro and in vivo in an animal model of lung fibrosis and should be considered as a potential therapeutic agent for systemic sclerosis and other fibrosing diseases.
机译：肝细胞生长因子受体，也称为细胞间质-上皮转化因子（c-MET，MET），是一种重要的抗纤维化分子，可保护包括肺在内的各种组织免受损伤和纤维化。 MET的细胞内细胞质尾包含一个caspase-3识别基序“ DEVD-T”，该基序在被caspase-3切割后产生一个10个氨基酸的肽TRPASFWETS，称为“ M10”。 M10在其N末端直接在阳离子氨基酸精氨酸（R）之后包含不带电荷的氨基酸脯氨酸（P），这有利于肽通过膜的运输。当添加到细胞培养基中时，M10会在细胞的细胞质和细胞核中保留长达24小时。 M10可有效减少硬皮病和TGFβ刺激的正常肺和皮肤成纤维细胞中的胶原蛋白。 M10与Smad2的Mad Homology 2域相互作用，并抑制TGFβ诱导的Smad2磷酸化，表明M10的抗纤维化作用部分是通过抵消Smad依赖的纤维化途径来介导的。在博来霉素鼠肺纤维化模型中，M10明显减少了肺部炎症和纤维化。与接受杂乱肽的博来霉素治疗的小鼠相比，接受M10的博来霉素治疗的小鼠的Ashcroft纤维化评分和肺胶原含量明显更低。我们得出结论，在肺纤维化动物模型中，M10肽与Smad2相互作用并在体外和体内显示出强大的抗纤维化作用，因此应被视为全身性硬化症和其他纤维化疾病的潜在治疗剂。

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