title: M10, a caspase cleavage product of the hepatocyte growth factor receptor, interacts with Smad2 and demonstrates antifibrotic properties in vitro and in vivo.
abstract: 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.
authors.affiliation: Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Ilia
authors.initials: I
authors.lastname: Atanelishvili
authors.affiliation: Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA; Department of Allergy and Rheumatology, Nippon Medical School, Tokyo, Japan.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Shirai
authors.affiliation: Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Tanjina
authors.initials: T
authors.lastname: Akter
authors.affiliation: Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA; South Carolina Governor's School for Science & Mathematics; Honors College at the College of Charleston, USA.
authors.forename: Taylor
authors.initials: T
authors.lastname: Buckner
authors.affiliation: Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Noguchi
authors.affiliation: Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Silver
authors.affiliation: Division of Rheumatology and Immunology, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA. Electronic address: bogatkev@musc.edu.
authors.forename: Galina S
authors.initials: GS
authors.lastname: Bogatkevich
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008168:Lung / Q000166:cytology; D008297:Male; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D011658:Pulmonary Fibrosis / Q000188:drug therapy / Q000473:pathology; D012595:Scleroderma, Systemic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D012867:Skin / Q000166:cytology; D051899:Smad2 Protein / Q000378:metabolism*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D010446:Peptide Fragments; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D003094:Collagen; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D053148:Caspase 3