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Met/Hepatocyte growth factor receptor ubiquitination suppresses transformation and is required for Hrs

Jasmine V Abella1, Pascal Peschard, Monica A Naujokas

  • 1Molecular Oncology Group H5.21, Department of Biochemistry, McGill University Health Centre, 687 Pine Avenue West, Montréal, Québec, Canada H3A 1A1.

Molecular and Cellular Biology
|October 18, 2005
PubMed

Insights

Impaired ubiquitination of the Met receptor tyrosine kinase (RTK) leads to sustained activation and tumorigenesis. Cbl-dependent ubiquitination is critical for Met receptor lysosomal sorting and suppressing its transforming activity.

Area of Science:

  • Oncology
  • Cell Biology
  • Molecular Biology

Background:

  • The Met receptor tyrosine kinase (RTK) plays a crucial role in epithelial cell functions.
  • Dysregulation of Met RTK is implicated in various human cancers.
  • Proper Met receptor down-regulation, involving ubiquitination and lysosomal degradation, is essential for controlling its activity.

Purpose of the Study:

  • To investigate the role of ubiquitination in Met receptor down-regulation and its impact on tumorigenesis.
  • To elucidate the mechanism by which ubiquitination targets Met for degradation and suppresses its transforming activity.

Main Methods:

  • Generated a ubiquitination-deficient Met receptor mutant (Y1003F).
  • Analyzed Met Y1003F internalization, endosomal trafficking, and degradation kinetics.
  • Assessed downstream signaling pathways, including Ras-MAPK and MEK1/2 activation.
  • Investigated the interaction of Met Y1003F with Hrs and the effect of monoubiquitin fusion.

Main Results:

  • The Met Y1003F mutant is internalized and trafficked similarly to wild-type Met but is inefficiently degraded.
  • Sustained activation of Met Y1003F leads to Ras-MAPK pathway activation, cell transformation, and tumorigenesis.
  • Fusion of monoubiquitin to Met Y1003F restores lysosomal targeting, suppresses MEK1/2 activation, and reduces transformation.

Conclusions:

  • Cbl-dependent ubiquitination is not required for Met receptor internalization but is critical for lysosomal sorting.
  • Ubiquitination is essential for targeting Met to the lysosomal degradation pathway and suppressing its oncogenic potential.
  • Targeting Met ubiquitination represents a potential therapeutic strategy for Met-driven cancers.

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