mTOR Repression in Response to Amino Acid Starvation Promotes ECM Degradation Through MT1-MMP Endocytosis Arrest.
mTOR Repression in Response to Amino Acid Starvation Promotes ECM Degradation Through MT1-MMP Endocytosis Arrest.
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DOI：
10.1002/advs.202101614
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发表时间：
2021-09
期刊：
影响因子：
--
通讯作者：
Chavrier P
中科院分区：
文献类型：
--
作者：
Colombero C;Remy D;Antoine-Bally S;Macé AS;Monteiro P;ElKhatib N;Fournier M;Dahmani A;Montaudon E;Montagnac G;Marangoni E;Chavrier P
在饥饿的条件下，正常和肿瘤上皮细胞可以将其代谢重新导向细胞外蛋白质的消耗，包括作为营养源的细胞外基质衍生成分。细胞周围基质降解的机制，饥饿的细胞已在很大程度上被忽视。本文显示，在氨基酸和生长因子剥夺后，乳腺和胰腺肿瘤细胞和患者来源的异种移植物外植体的基质降解增加了一个数量级。此外，发现胶原溶解需要侵袭伪足组分TKS 5和跨膜金属蛋白酶MT 1-MMP，这是肿瘤侵袭程序的关键。增加的胶原溶解由营养耗尽后的mTOR抑制或雷帕霉素的药理学抑制控制。结果表明，饥饿阻碍了网格蛋白介导的内吞作用，导致MT 1-MMP在被捕的网格蛋白包被的凹坑中积累。该研究揭示了一种新的机制，即饥饿细胞中的mTOR抑制导致丰富的质膜网格蛋白包被的凹坑重新利用为稳健的ECM降解组件。当营养物耗尽时，癌细胞分解代谢细胞外基质（ECM）组分以维持生长。这项研究报告说，肿瘤细胞重新利用侵袭伪足，蛋白酶依赖性程序，以引发大量的ECM降解机制，在雷帕霉素复合物1的机制靶点的调节下。营养缺乏阻断了膜型1-基质金属蛋白酶的内吞作用，将被捕的网格蛋白包被的小凹转化为强大的基质降解单位。
Under conditions of starvation, normal and tumor epithelial cells can rewire their metabolism toward the consumption of extracellular proteins, including extracellular matrix‐derived components as nutrient sources. The mechanism of pericellular matrix degradation by starved cells has been largely overlooked. Here it is shown that matrix degradation by breast and pancreatic tumor cells and patient‐derived xenograft explants increases by one order of magnitude upon amino acid and growth factor deprivation. In addition, it is found that collagenolysis requires the invadopodia components, TKS5, and the transmembrane metalloproteinase, MT1‐MMP, which are key to the tumor invasion program. Increased collagenolysis is controlled by mTOR repression upon nutrient depletion or pharmacological inhibition by rapamycin. The results reveal that starvation hampers clathrin‐mediated endocytosis, resulting in MT1‐MMP accumulation in arrested clathrin‐coated pits. The study uncovers a new mechanism whereby mTOR repression in starved cells leads to the repurposing of abundant plasma membrane clathrin‐coated pits into robust ECM‐degradative assemblies. Cancer cells catabolize extracellular matrix (ECM) components to maintain growth when nutrients are depleted. This study reports that tumor cells repurpose the invadopodia‐, protease‐dependent program to elicit a massive ECM degradation mechanism, under regulation by mechanistic target of rapamycin complex 1. Nutrient scarcity blocks endocytosis of membrane type 1‐matrix metalloproteinase converting arrested clathrin‐coated pits into powerful matrix degradation units.
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DOI：
10.1038/nrm3141
发表时间：
2011-06-23
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
16.6
作者：
Infante E;Castagnino A;Ferrari R;Monteiro P;Agüera-González S;Paul-Gilloteaux P;Domingues MJ;Maiuri P;Raab M;Shanahan CM;Baffet A;Piel M;Gomes ER;Chavrier P
通讯作者：
Chavrier P
影响因子：
82.9
作者：
Davidson SM;Jonas O;Keibler MA;Hou HW;Luengo A;Mayers JR;Wyckoff J;Del Rosario AM;Whitman M;Chin CR;Condon KJ;Lammers A;Kellersberger KA;Stall BK;Stephanopoulos G;Bar-Sagi D;Han J;Rabinowitz JD;Cima MJ;Langer R;Vander Heiden MG
通讯作者：
Vander Heiden MG
影响因子：
16.6
作者：
Olivares O;Mayers JR;Gouirand V;Torrence ME;Gicquel T;Borge L;Lac S;Roques J;Lavaut MN;Berthezène P;Rubis M;Secq V;Garcia S;Moutardier V;Lombardo D;Iovanna JL;Tomasini R;Guillaumond F;Vander Heiden MG;Vasseur S
通讯作者：
Vasseur S
影响因子：
64.5
作者：
Demetriades C;Doumpas N;Teleman AA
通讯作者：
Teleman AA