Author:

Keywords:

hepatocyte growth-factor, macrophage-stimulating protein, c-met protooncogene, epithelial-cells, factor receptor, factor/scatter factor, proteolytic cleavage, alpha-chain, beta-chain, ron gene, Science & Technology, Life Sciences & Biomedicine, Biotechnology & Applied Microbiology, HEPATOCYTE GROWTH-FACTOR, MACROPHAGE-STIMULATING PROTEIN, C-MET PROTOONCOGENE, PROTEOLYTIC CLEAVAGE, FACTOR RECEPTOR, RON GENE, OVEREXPRESSION, MORPHOGENESIS, LIGAND, METASTASIS, Animals, Apoptosis, Blotting, Western, Cell Division, Cell Line, Cross-Linking Reagents, Cytokines, Dimerization, Dose-Response Relationship, Drug, Epithelial Cells, Growth Substances, Hepatocyte Growth Factor, Humans, Kidney, Ligands, Mice, Models, Biological, Protein Binding, Proto-Oncogene Proteins, Receptors, Growth Factor, Recombinant Fusion Proteins, Renal Insufficiency, Signal Transduction, Time Factors

Abstract:

Hepatocyte growth factor (HGF) and macrophage-stimulating protein (MSP) have an intrinsic dual nature: they are trophic cytokines preventing apoptosis on one side and scatter factors promoting invasion on the other. For therapeutic use, their anti-apoptotic activity must be separated from their pro-invasive activity. To this end, we engineered chimeric factors containing selected functional domains of HGF and/or MSP in different combinations, and tested their biological activity. Here we present a chimeric cytokine derived from the chains of HGF and MSP, named Metron factor 1 for its ability to concomitantly activate the HGF receptor (Met) and the MSP receptor (Ron). We provide evidence that Metron factor 1 prevents apoptosis and stimulates cell proliferation at nanomolar concentrations, but is devoid of any pro-invasive activity. In an in vivo murine model of drug-induced nephrotoxicity, intravenous injection of recombinant Metron factor 1 prevented renal damage and preserved tubular integrity.