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Loss of human Scribble cooperates with H-Ras to promote cell invasion through deregulation of MAPK signalling

L E Dow1, I A Elsum, C L King

  • 1Research Division, Cell Cycle and Cancer Genetics, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

Oncogene
|July 22, 2008
PubMed

Insights

Loss of Scribble, a polarity regulator, promotes cancer cell invasion by affecting Ras-mitogen-activated protein kinase (MAPK) signaling. This finding explains why Scribble is often decreased in invasive human cancers.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Oncology

Background:

  • Activating mutations in the Ras-mitogen-activated protein kinase (MAPK) pathway are common in human cancers but rarely sufficient for tumor development.
  • Scribble, a polarity regulator, cooperates with Ras mutations to promote tumor progression and cell invasion in Drosophila.
  • Mammalian Scribble's role in oncogenic transformation was previously unidentified, despite its known roles in cell migration and wound healing.

Purpose of the Study:

  • To investigate the role of mammalian Scribble in oncogenic transformation and its relationship with Ras-MAPK signaling.
  • To determine the mechanism by which Scribble loss affects cancer cell invasion.
  • To explore the conserved function of Scribble in regulating MAPK signaling.

Main Methods:

  • Utilized organotypic culture systems with human epithelial cells expressing oncogenic Ras or Raf.
  • Assessed cell invasion through extracellular matrix.
  • Investigated the regulation of MAPK signaling by Scribble in both human cells and Drosophila models.

Main Results:

  • Loss of Scribble significantly promoted invasion of human epithelial cells expressing oncogenic Ras or Raf through extracellular matrix.
  • Scribble regulates MAPK signaling, and its loss leads to enhanced MAPK signaling, promoting invasion.
  • Scribble's function in suppressing MAPK signaling is conserved, as it prevents Raf-mediated defects in Drosophila wing development.

Conclusions:

  • Scribble is an important mediator of MAPK signaling in the context of oncogenic transformation.
  • Loss of Scribble promotes cancer cell invasion by dysregulating MAPK signaling.
  • Decreased Scribble expression in invasive human cancers is linked to its role in suppressing oncogenic MAPK signaling.

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