1] Centre for Tumour Biology, Barts Cancer Institute-a Cancer Research UK Centre of Excellence, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London EC1M 6BQ, UK [2] Protein Phosphorylation Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
1] Protein Phosphorylation Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK [2] Division of Cancer Studies, King's College School of Medicine, Guy's Hospital, Thomas Street, London SE1 9RT, UK.
Nat Commun. 2014 May 19;5:3907. doi: 10.1038/ncomms4907.
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.
受体酪氨酸激酶 (RTKs) 越来越被认为具有在细胞内内化后的信号转导能力。人们认为，与来自质膜的信号转导相比，从内体发出的信号转导输出和/或持续时间以及随后的细胞结果是不同的。在这里，我们在侵袭性、基底样人乳腺细胞模型中表明，不同的机制被 RTK c-Met 用于两个不同的内体，通过关键的迁移信号输出 Rac1 来控制肌动蛋白细胞骨架。尽管 Rac1 从外周内体 (PE) 中被急性激活，但 c-Met 需要运输到核周内体 (PNE) 以维持 Rac1 信号转导，触发最佳的膜皱襞、细胞迁移和侵袭。出乎意料的是，在 PNE 中而不是在 PE 中，PI3K 和 Rac-GEF Vav2 是必需的。因此，我们描述了一种新的内体信号转导机制，其中同一个 RTK 通过不同的途径刺激一种信号输出 Rac1，这取决于它在细胞中位于哪个内体。
