Control of cell death/survival balance by the MET dependence receptor
Control of cell death/survival balance by the MET dependence receptor
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DOI：
10.7554/elife.50041
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发表时间：
2020-02-24
期刊：
影响因子：
7.7
通讯作者：
Tulasne, David
中科院分区：
文献类型：
--
作者：
Duplaquet, Leslie;Leroy, Catherine;Tulasne, David
细胞死亡/存活平衡的控制是维持组织稳态的重要特征。依赖性受体能够在存在或不存在其配体的情况下分别诱导存活或细胞死亡。然而，它们的精确作用机制和它们的生理重要性对于它们中的大多数包括MET受体仍然是难以捉摸的。我们的证据表明，促凋亡片段产生的半胱天冬酶切割MET定位到细胞膜相关的区域。该片段触发钙从内质网转移到线粒体，这有助于受体的凋亡作用。携带MET半胱天冬酶切割位点突变的敲入小鼠强调了p40 MET的产生对于FAS驱动的肝细胞凋亡是重要的，并证明MET在体内充当依赖性受体。我们的数据揭示了依赖性受体控制细胞生存/死亡平衡的新信号机制，这可能为上皮结构的病理生理学提供新的线索。
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.