Receptor tyrosine kinase c-Met controls the cytoskeleton from different endosomes via different pathways
Receptor tyrosine kinase c-Met controls the cytoskeleton from different endosomes via different pathways
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DOI：
10.1038/ncomms4907
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发表时间：
2014-05-01
影响因子：
16.6
通讯作者：
Kermorgant, Stephanie
中科院分区：
文献类型：
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作者：
Menard, Ludovic;Parker, Peter J.;Kermorgant, Stephanie
人们越来越认识到受体酪氨酸激酶 (RTK) 具有内化后发出信号的能力。与来自质膜的信号输出和/或持续时间以及随后的细胞结果相比，从内体发出的信号输出和/或持续时间以及随后的细胞结果被认为是不同的。在这里，我们表明，在侵入性基底细胞样人类乳腺细胞模型中，两种不同内体中的 RTK c-Met 发挥不同的机制，通过关键的迁移信号输出 Rac1 控制肌动蛋白细胞骨架。尽管 Rac1 从外周内体 (PE) 急剧激活，但 c-Met 需要转运至核周内体 (PNE) 以维持 Rac1 信号传导，触发最佳的膜皱褶、细胞迁移和侵袭。出乎意料的是，在 PNE 中而不是在 PE 中，需要 PI3K 和 Rac-GEF Vav2。因此，我们描述了一种新的内体信号传导机制，其中一个信号输出 Rac1 通过不同的途径被相同的 RTK 刺激，具体取决于它在细胞中定位于哪个内体。
Receptor tyrosine kinases (RTKs) are increasingly recognized as having the capacity to signal post-internalization. Signalling outputs and/or duration, and subsequent cellular outcome, are thought to be distinct when emanating from endosomes compared with those from the plasma membrane. Here we show, in invasive, basal-like human breast cell models, that different mechanisms are engaged by the RTK c-Met in two different endosomes to control the actin cytoskeleton via the key migratory signal output Rac1. Despite an acute activation of Rac1 from peripheral endosomes (PEs), c-Met needs to traffic to a perinuclear endosome (PNE) to sustain Rac1 signalling, trigger optimal membrane ruffling, cell migration and invasion. Unexpectedly, in the PNE but not in the PE, PI3K and the Rac-GEF Vav2 are required. Thus we describe a novel endosomal signalling mechanism whereby one signal output, Rac1, is stimulated through distinct pathways by the same RTK depending on which endosome it is localized to in the cell.