Receptor tyrosine kinase c-Met controls the cytoskeleton from different endosomes via different pathways

Ludovic Ménard, Peter J. Parker and Stéphanie Kermorgant ()
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Ludovic Ménard: Centre for Tumour Biology, Barts Cancer Institute—a Cancer Research UK Centre of Excellence, Queen Mary University of London, John Vane Science Centre
Peter J. Parker: Protein Phosphorylation Laboratory, Cancer Research UK London Research Institute
Stéphanie Kermorgant: Centre for Tumour Biology, Barts Cancer Institute—a Cancer Research UK Centre of Excellence, Queen Mary University of London, John Vane Science Centre

Nature Communications, 2014, vol. 5, issue 1, 1-14

Abstract: Abstract 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.

Date: 2014
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DOI: 10.1038/ncomms4907

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