Caspase-generated fragment of the Met receptor favors apoptosis via the intrinsic pathway independently of its tyrosine kinase activity

Lefebvre, J. et al. (2013) Caspase-generated fragment of the Met receptor favors apoptosis via the intrinsic pathway independently of its tyrosine kinase activity. Cell Death and Disease, 4(10), e871. (doi: 10.1038/cddis.2013.377)

Abstract

The receptor tyrosine kinase Met and its ligand, the hepatocyte growth factor, are essential to embryonic development, whereas the deregulation of Met signaling is associated with tumorigenesis. While ligand-activated Met promotes survival, caspase-dependent generation of the p40 Met fragment leads to apoptosis induction – hallmark of the dependence receptor. Although the survival signaling pathways induced by Met are well described, the pro-apoptotic signaling pathways are unknown. We show that, although p40 Met contains the entire kinase domain, it accelerates apoptosis independently of kinase activity. In cell cultures undergoing apoptosis, the fragment shows a mitochondrial localization, required for p40 Met-induced cell death. Fulminant hepatic failure induced in mice leads to the generation of p40 Met localized also in the mitochondria, demonstrating caspase cleavage of Met in vivo. According to its localization, the fragment induces mitochondrial permeabilization, which is inhibited by Bak silencing and Bcl-xL overexpression. Moreover, Met silencing delays mitochondrial permeabilization induced by an apoptotic treatment. Thus, the Met-dependence receptor in addition to its well-known role in survival signaling mediated by its kinase activity, also participates in the intrinsic apoptosis pathway through the generation of p40 Met – a caspase-dependent fragment of Met implicated in the mitochondrial permeabilization process.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Ichim, Dr Gabriel
• Authors: Lefebvre, J., Muharram, G., Leroy, C., Kherrouche, Z., Montagne, R., Ichim, G., Tauszig-Delamasure, S., Chotteau-Lelievre, A., Brenner, C., Mehlen, P., and Tulasne, D.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Cell Death and Disease
• Publisher: Nature Publishing Group
• ISSN: 2041-4889
• ISSN (Online): 2041-4889
• Copyright Holders: Copyright © 2013 The Authors
• Publisher Policy: First published in Cell Death and Disease 4(10):e871