Ligand-Occupied Integrin Internalization Links Nutrient Signaling to Invasive Migration
Ligand-Occupied Integrin Internalization Links Nutrient Signaling to Invasive Migration
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DOI：
10.1016/j.celrep.2014.12.037
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发表时间：
2015-01-20
期刊：
影响因子：
8.8
通讯作者：
Norman, Jim C.
中科院分区：
文献类型：
--
作者：
Rainero, Elena;Howe, Jonathan D.;Norman, Jim C.
整合素的运输是细胞迁移的关键，但对整合素内吞作用的时空组织知之甚少。在这里，我们表明，α 5 β 1整合素经历张力依赖性的向心运动，从细胞周边填充位于细胞核下的粘连。从这里开始，配体接合的α 5 β 1整联蛋白在Arf亚家族GTf、Arf 4的控制下内化，并被运输到附近的晚期内体/溶酶体。向心运动或Arf 4依赖性内吞作用的抑制破坏了配体结合的整合素向晚期内体/溶酶体的流动及其在该隔室内的降解。Arf 4依赖性整合素内化是适当的溶酶体定位和募集和激活mTOR在这个细胞亚室所必需的。此外，营养消耗通过抑制mTORC 1促进配体接合的α 5 β 1整联蛋白的亚核积累和内吞作用。mTORC 1和整合素运输之间的这种双向调节相互作用结合描述张力蛋白在侵入性细胞迁移中的作用的数据表明营养信号传导和转移之间的有趣联系。
Integrin trafficking is key to cell migration, but little is known about the spatiotemporal organization of integrin endocytosis. Here, we show that alpha 5 beta 1 integrin undergoes tensin-dependent centripetal movement from the cell periphery to populate adhesions located under the nucleus. From here, ligand-engaged alpha 5 beta 1 integrins are internalized under control of the Arf subfamily GTPase, Arf4, and are trafficked to nearby late endosomes/lysosomes. Suppression of centripetal movement or Arf4-dependent endocytosis disrupts flow of ligand-bound integrins to late endosomes/lysosomes and their degradation within this compartment. Arf4-dependent integrin internalization is required for proper lysosome positioning and for recruitment and activation of mTOR at this cellular subcompartment. Furthermore, nutrient depletion promotes subnuclear accumulation and endocytosis of ligand-engaged alpha 5 beta 1 integrins via inhibition of mTORC1. This two-way regulatory interaction between mTORC1 and integrin trafficking in combination with data describing a role for tensin in invasive cell migration indicate interesting links between nutrient signaling and metastasis.