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

Ludovic Ménard1, Peter J Parker2, Stéphanie Kermorgant3

  • 11] 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.

Nature Communications
|May 20, 2014
PubMed

Insights

Receptor tyrosine kinases (RTKs) signal differently from distinct endosomes. The RTK c-Met requires perinuclear endosomes for sustained Rac1 signaling, controlling cell migration and invasion.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Receptor tyrosine kinases (RTKs) can signal after internalization from the plasma membrane.
  • Endosomal signaling platforms are emerging as critical regulators of cellular processes.
  • Distinct signaling outcomes are hypothesized based on RTK localization within endosomes.

Purpose of the Study:

  • To investigate the distinct roles of endosomal localization of the RTK c-Met in controlling cell migration.
  • To elucidate the specific endosomal mechanisms regulating the actin cytoskeleton and cell invasion.
  • To identify signaling pathways differentially engaged by c-Met in distinct endosomal compartments.

Main Methods:

  • Utilized invasive basal-like human breast cancer cell models.
  • Investigated the signaling of the RTK c-Met in peripheral endosomes (PEs) and perinuclear endosomes (PNEs).
  • Analyzed the activation of Rac1, actin cytoskeleton dynamics, membrane ruffling, cell migration, and invasion.

Main Results:

  • c-Met activation of Rac1 is acute from PEs but requires trafficking to PNEs for sustained signaling.
  • Sustained Rac1 signaling from PNEs is essential for optimal membrane ruffling, cell migration, and invasion.
  • PI3K and the Rac-GEF Vav2 are specifically required for c-Met signaling in PNEs, but not PEs.

Conclusions:

  • RTK signaling is compartmentalized within distinct endosomal populations.
  • c-Met utilizes different endosomal pathways to regulate Rac1 and control cell migration and invasion.
  • This study reveals a novel mechanism of endosomal signal diversification by RTKs.

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