Control of cell death/survival balance by the MET dependence receptor
Leslie Duplaquet1, Catherine Leroy1, Audrey Vinchent1
1Univ. Lille, CNRS, Institut Pasteur de Lille, UMR 8161 - M3T - Mechanisms of Tumorigenesis and Targeted Therapies, Lille, France.
Abstract:
Control of cell death/survival balance is an important feature to maintain tissue homeostasis. Dependence receptors are able to induce either survival or cell death in presence or absence of their ligand, respectively. However, their precise mechanism of action and their physiological importance are still elusive for most of them including the MET receptor. We evidence that pro-apoptotic fragment generated by caspase cleavage of MET localizes to the mitochondria-associated membrane region. This fragment triggers a calcium transfer from endoplasmic reticulum to mitochondria, which is instrumental for the apoptotic action of the receptor. Knock-in mice bearing a mutation of MET caspase cleavage site highlighted that p40MET production is important for FAS-driven hepatocyte apoptosis, and demonstrate that MET acts as a dependence receptor in vivo. Our data shed light on new signaling mechanisms for dependence receptors' control of cell survival/death balance, which may offer new clues for the pathophysiology of epithelial structures.
Insights
The MET receptor, a dependence receptor, controls cell death by releasing a fragment that triggers calcium transfer to mitochondria. This mechanism is vital for tissue homeostasis and hepatocyte apoptosis in vivo.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- Maintaining cellular survival and death balance is crucial for tissue homeostasis.
- Dependence receptors regulate cell fate (survival/death) based on ligand presence.
- The precise functions and mechanisms of dependence receptors, like MET, remain unclear.
Purpose of the Study:
- To elucidate the mechanism of action of the MET receptor as a dependence receptor.
- To investigate the role of MET in regulating cell death and survival.
- To understand the physiological importance of MET in vivo.
Main Methods:
- Investigated the localization of MET's pro-apoptotic fragment using cellular and biochemical assays.
- Analyzed calcium transfer between the endoplasmic reticulum and mitochondria.
- Utilized knock-in mice with a mutated MET caspase cleavage site to study in vivo apoptosis.
Main Results:
- The pro-apoptotic fragment of MET (p40MET) localizes to the mitochondria-associated membrane.
- This fragment induces calcium transfer from the endoplasmic reticulum to mitochondria, promoting apoptosis.
- MET is demonstrated to function as a dependence receptor in vivo, crucial for FAS-driven hepatocyte apoptosis.
Conclusions:
- MET's pro-apoptotic fragment mediates cell death by regulating mitochondrial calcium influx.
- MET acts as a dependence receptor in vivo, influencing hepatocyte apoptosis.
- These findings reveal novel signaling pathways for dependence receptors and offer insights into epithelial pathophysiology.
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