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Cortactin overexpression inhibits ligand-induced down-regulation of the epidermal growth factor receptor

Paul Timpson1, Danielle K Lynch, Daniel Schramek

  • 1Cancer Research Program, Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, New South Wales 2010, Australia.

Cancer Research
|April 19, 2005
PubMed

Insights

Cortactin overexpression inhibits epidermal growth factor receptor (EGFR) down-regulation, prolonging signaling. Reducing cortactin accelerates EGFR degradation, impacting cancer progression.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Cancer Research

Background:

  • Receptor tyrosine kinase (RTK) signaling, like that of the epidermal growth factor receptor (EGFR), is regulated by ligand-induced down-regulation via endocytosis.
  • Ubiquitylation, mediated by E3 ubiquitin ligases such as c-Cbl, targets RTKs for lysosomal degradation, terminating signaling.
  • Cortactin, encoded by the amplified EMS1 gene in cancers, links endocytosis to actin dynamics and promotes tumor invasion.

Purpose of the Study:

  • To investigate the role of cortactin in regulating ligand-induced epidermal growth factor receptor (EGFR) down-regulation.
  • To determine the impact of cortactin overexpression on EGFR signaling pathways and ubiquitylation.
  • To explore the association between cortactin levels and EGFR signaling in head and neck squamous cell carcinoma (HNSCC).

Main Methods:

  • Overexpression of cortactin in HeLa cells to assess effects on EGFR down-regulation and signaling.
  • Analysis of c-Cbl phosphorylation and association with EGFR.
  • Measurement of EGFR ubiquitylation and extracellular signal-regulated kinase (ERK) activation.
  • Examination of cortactin expression and EGFR down-regulation in HNSCC cell lines.
  • RNA interference (RNAi) to reduce cortactin expression in HNSCC cells.

Main Results:

  • Cortactin overexpression in HeLa cells significantly inhibited ligand-induced EGFR down-regulation.
  • This inhibition was independent of EGFR autophosphorylation and correlated with impaired c-Cbl phosphorylation and association with EGFR.
  • EGFR ubiquitylation was reduced, leading to sustained EGF-induced ERK activation.
  • Cortactin overexpression in HNSCC cell lines was associated with attenuated EGFR down-regulation.
  • RNAi-mediated reduction of cortactin accelerated EGFR degradation in an HNSCC cell line.

Conclusions:

  • Cortactin overexpression disrupts EGFR down-regulation by interfering with the c-Cbl-mediated ubiquitylation and lysosomal degradation pathway.
  • Sustained EGFR signaling due to cortactin overexpression may contribute to tumor progression and provides a potential explanation for EMS1 gene amplification in cancers.
  • This study demonstrates, for the first time, that cortactin modulates growth factor receptor signaling.

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