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Regulation of the MET receptor tyrosine kinase functions through proteolytic cleavages – MET Cleavages

Submission summary

The hepatocyte growth factor/ scatter factor (HGF/SF) acts through the MET tyrosine kinase receptor to promote survival, proliferation or motility of epithelial cells during normal development and tumour progression. Upon HGF/SF binding, the tyrosine kinase activity of MET is stimulated with autophosphorylation of the receptor, leading to activation of multiple intracellular signalling pathways. Number groups study the biological responses induced by the full length MET activated by its ligand and its subsequent signalling pathways. However various fragments or truncated MET receptors have been described as well, but their functional involvements were not further characterised. Our recent data revealed original caspase cleavages of MET, leading to generation of a pro-apoptotic fragment able to amplify apoptosis. In addition, we showed that MET is cleaved as well by -secretase, generating fragment able to translocate in the nucleus. Although caspase and secretase cleavages do not occur in the same conditions and that the fragments generated are distinct, it lead us to investigate the MET signalling through the original point of view of the proteolytic cleavages. Furthermore, our data demonstrate that proteolytic cleavages of MET generate active fragment with unexpected biological functions. We propose for both caspase and secretase cleavages to determine the physiological conditions in which cleavages occur. We will characterise the mechanisms of cleavage including the nature of the proteases and the cleavage sites, by using pharmacological inhibitors, cells deficient in determine protease or mutated forms of MET. We will search as well to identify the physiological functions of the fragments or truncated receptors, by expressing them notably in epithelial cells and by generating genetically modified mice expressing uncleavable MET. The aim of this project is to understand the balance survival/apoptosis mediated by MET, which contributes to epithelial homeostasis involved in development and tumour progression. In addition, this study could reveal novel functions or original signalling mechanisms mediated by MET receptor through its proteolytic cleavages.

Project coordination

david TULASNE (Organisme de recherche)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

Help of the ANR 150,000 euros
Beginning and duration of the scientific project: - 36 Months

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