M10, a caspase cleavage product of the hepatocyte growth factor receptor, interacts with Smad2 and demonstrates antifibrotic properties in vitro and in vivo.
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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DOI：
10.1016/j.trsl.2015.12.009
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发表时间：
2016-04
期刊：
影响因子：
--
通讯作者：
Bogatkevich GS
中科院分区：
文献类型：
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作者：
Atanelishvili I;Shirai Y;Akter T;Buckner T;Noguchi A;Silver RM;Bogatkevich GS
肝细胞生长因子受体，也称为细胞间充质-上皮转化因子（c-MET，MET），是一种重要的抗纤维化分子，可以保护包括肺在内的各种组织免受损伤和纤维化。 The intracellular cytoplasmic tail of MET contains a caspase-3 recognition motif “DEVD-T” that upon cleavage by caspase-3 generates a 10 amino acid peptide, TRPASFWETS, designated as “M10”. M10 在其 N 末端包含紧接在阳离子氨基酸精氨酸 (R) 后面的不带电氨基酸脯氨酸 (P)，这有利于肽通过膜的转运。当添加到细胞培养基中时，M10 可在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 MH2 结构域相互作用，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 依赖性纤维形成途径介导的。在博来霉素小鼠肺纤维化模型中，M10 显着减少肺部炎症和纤维化。与接受乱序肽的博莱霉素治疗小鼠相比，接受 M10 的博莱霉素治疗小鼠的 Ashcroft 纤维化评分和肺胶原含量显着降低。我们得出的结论是，M10 肽与 Smad2 相互作用，并在肺纤维化动物模型中在体外和体内表现出强大的抗纤维化作用，应被视为系统性硬化症和其他纤维化疾病的潜在治疗剂。
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 upon 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 TGFβ-stimulated normal lung and skin fibroblasts. M10 interacts with the MH2 domain of Smad2 and inhibits TGFβ-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.