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

TY - JOUR

T1 - Receptor tyrosine kinase c-Met controls the cytoskeleton from different endosomes via different pathways

AU - Menard, Ludovic

AU - Parker, Peter J.

AU - Kermorgant, Stephanie

PY - 2014/5/19

Y1 - 2014/5/19

N2 - 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.

AB - 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.

KW - HEPATOCYTE GROWTH-FACTOR

KW - NEGATIVE BREAST-CARCINOMA

KW - TGF-BETA RECEPTOR

KW - CELL-MIGRATION

KW - SCATTER-FACTOR

KW - CANCER-CELLS

KW - SIGNAL-TRANSDUCTION

KW - INVASIVE GROWTH

KW - DOWN-REGULATION

KW - EXCHANGE-FACTOR

U2 - 10.1038/ncomms4907

DO - 10.1038/ncomms4907

M3 - Article

SN - 2041-1723

VL - 5

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3907

ER -