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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• 作者：Ilia Atanelishvili^a ; Yuichiro Shirai^a ; ^b ; Tanjina Akter^a ; Taylor Buckner^a ; ^c ; ^d ; Atsushi Noguchi^a ; Richard M. Silver^a ; Galina S. Bogatkevich^a ; ^{bogatkev@musc.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：HGF ; Hepatocyte growth factor ; c-MET ; MET ; mesenchymal-epithelial transition factor ; systemic sclerosis ; SSc ; scleroderma ; ILD ; interstitial lung disease ; IPF ; idiopathic pulmonary fibrosis ; TGFβ ; transforming growth factor beta ; PLC ; phospholipase C ; PKC ; protein kinase C ; DAPI ; 4&prime ; 6-diamidino-2-phenylindole ; MYC ; polypeptide protein tag consisted of EQKLISEEDL amino acids ; DDK ; polypeptide protein tag consisted of DYKDDDDK amino acids ; ACR ; American College of Rheumatology ; EULAR ; Europe
• 刊名：Translational Research
• 出版年：2016
• 出版时间：April 2016
• 年：2016
• 卷：170
• 期：Complete
• 页码：99-111
• 全文大小：2536 K

文摘

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 TGFβ-stimulated normal lung and skin fibroblasts. M10 interacts with the Mad Homology 2 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.