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Receptor trafficking controls weak signal delivery: a strategy used by c-Met for STAT3 nuclear accumulation

Stéphanie Kermorgant1, Peter J Parker

  • 1Department of Tumour Biology, Cancer Research UK Clinical Centre, Bart's and the London Queen Mary's School of Medicine and Dentistry, London EC1M 6BQ, England, UK.

The Journal of Cell Biology
|September 10, 2008
PubMed

Insights

Cancer therapy targeting C-Met requires understanding its signaling pathways. C-Met receptor trafficking to perinuclear endosomes sustains STAT3 activation in the nucleus, a novel finding for cancer intervention.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • C-Met is a protooncogene and a key target in cancer therapy.
  • Hepatocyte growth factor (HGF)/c-Met signaling drives tumorigenesis partly via Signal Transducer and Activator of Transcription 3 (STAT3).
  • STAT3 activation is typically thought to occur at the plasma membrane, followed by nuclear translocation.

Purpose of the Study:

  • To investigate the mechanism of STAT3 activation downstream of c-Met signaling.
  • To determine the role of receptor trafficking in signal transduction.
  • To explore novel therapeutic intervention points in cancer signaling.

Main Methods:

  • Cellular signaling analysis
  • Confocal microscopy to track receptor localization
  • Investigating STAT3 and extracellular signal-regulated kinase (ERK) nuclear accumulation

Main Results:

  • While robust STAT3 activation by oncostatin-M follows the canonical pathway, weaker STAT3 signals from c-Met require receptor trafficking to perinuclear endosomes.
  • Sustained STAT3 phosphorylation in the nucleus depends on this perinuclear localization of the activated c-Met receptor.
  • c-Met-induced nuclear accumulation of ERK is signal-specific and initiated from peripheral endosomes, unlike STAT3 signaling.

Conclusions:

  • The trafficking route of growth factor receptors dictates the specific signal output.
  • Perinuclear endosomal localization of c-Met is crucial for sustained STAT3 activation in the nucleus.
  • Controlling growth factor receptor traffic offers new strategies for cancer therapy.

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