Résumés disponibles (92) :

DUPLAQUET Leslie (UMR CNRS 8161 éq. 05 - David TULASNE)
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@mail :  leslie.duplaquet@ibl.cnrs.fr      tél. :  0675775892


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Titre de la communication :
The dark side of MET receptor : Impact on survival-apoptosis balance in vivo
Auteurs (et leurs adresses) de la communication :
Leslie Duplaquet - Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T – Mechanisms of Tumorigenesis and Target Therapies, F-59000 Lille, France
Résumé de la communication :
MET is a receptor tyrosine kinase (RTK) expressed predominantly by epithelial cells. Its high affinity ligand is the Hepatocyte Growth Factor (HGF). MET signaling pathways play a major role in epithelial homeostasis, embryogenesis and tissue regeneration in adult. MET is also a powerful oncogene able to promote tumor invasion and metastasis in many types of cancer. However, in absence of ligand, MET is also able to promote apoptosis through its caspase cleavage leading to the release of a 40kDa cytosolic pro-apoptotic fragment named p40MET. This fragment is able to activate the intrinsic pathway of apoptosis by inducing mitochondrial membrane permeabilization. While survival pathways induced by the ligand-activated MET are well described, the physiological relevance and mechanisms allowing p40MET to promote apoptosis are still unknown.

To understand the in vivo involvement of MET in apoptosis, we developed knock-in mice in which the receptor is mutated on a caspase site. From primary hepatocytes derived from these mice, we showed that mutation of MET caspase site induces reduction of the caspase 3 activation and a loss of mitochondrial membrane permeabilization resulting in a decrease of the apoptotic response. This demonstrates that MET cleavage plays an important role in cell death amplification. To further understand the mechanisms induced by p40MET to promote apoptosis, we characterize its subcellular localization. Interestingly, p40MET is localized at the interface between the endoplasmic reticulum (ER) and mitochondria, a subcellular domain involved in calcium exchanges between these organelles. Consistently, p40MET is able to induce calcium leakage from ER and its recapture by mitochondria that ultimately induces mitochondria permeabilization and liberation of pro-apoptotic factors. Futhermore, inhibition of the calcium exchange abrogates apoptosis induced by the fragment shown by the decrease of both caspase 3 activation and mitochondrial membrane permeabilization.

Thus, our work demonstrates that in addition to its ability to induce survival, MET is involved in the amplification of apoptosis evidenced in primary hepatocyte from knock-in mice, through an original mechanism involving calcium exchange between ER and mitochondria. The dual competence of MET able to induce either survival or apoptosis depending to cellular context allow us to classify MET among the dependence receptors. This characteristic has important consequences on the role of MET during tumorigenesis. Indeed, in cancer the survival/apoptosis balance leans towards survival, the interest will be therefore to inhibit pro-survival signaling of the receptor while retaining its pro-apoptotic capacities.

DUPLAQUET Leslie (UMR CNRS 8161 éq. 05 - David TULASNE)