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Endosomal accumulation of the activated epidermal growth factor receptor (EGFR) induces apoptosis

Jamie S Rush1, Leslie M Quinalty1, Luke Engelman1

  • 1Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, 73106.

The Journal of Biological Chemistry
|November 22, 2011
PubMed

Insights

Cell surface epidermal growth factor receptors (EGFRs) promote growth, but when trapped on endosomes, they trigger apoptosis. This study reveals endosomal membrane localization of EGFRs dictates cell fate.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Endocytosis regulates cell surface receptor signaling by controlling interactions with downstream effectors.
  • The precise link between receptor endocytic trafficking and cell physiology remains largely undefined.
  • Epidermal Growth Factor Receptors (EGFRs) play crucial roles in cell growth and survival, with dysregulation implicated in various cancers.

Purpose of the Study:

  • To investigate the role of EGFR endocytic trafficking in regulating cell fate, specifically apoptosis.
  • To elucidate the mechanism by which EGFR localization within endosomes influences cellular responses.
  • To determine if disrupting EGFR trafficking can induce apoptosis in cells not typically sensitive to EGF-induced cell death.

Main Methods:

  • Utilized MDA-MB-468 cells, a model system with distinct EGFR signaling responses (growth vs. apoptosis).
  • Employed pharmacological and biochemical strategies to perturb EGFR endocytic trafficking in both MDA-MB-468 and HeLa cells.
  • Analyzed EGFR localization, phosphorylation status, and cellular responses (apoptosis) under manipulated trafficking conditions.

Main Results:

  • In MDA-MB-468 cells, phosphorylated EGFR accumulated on the endosomal limiting membrane, with its carboxyl terminus facing the cytoplasm.
  • Disruption of EGFR trafficking in HeLa cells to accumulate active EGF·EGFR complexes on the endosomal limiting membrane sustained receptor phosphorylation and induced apoptosis.
  • Accumulation of EGF·EGFR complexes within intraluminal vesicles of late endosomes did not sustain phosphorylation or induce apoptosis.

Conclusions:

  • EGFR-mediated apoptosis is initiated specifically by activated EGFRs localized on the limiting membrane of endosomes.
  • The spatial arrangement of EGFRs within the endocytic pathway is critical for determining cell fate.
  • Endosomal trafficking of EGFRs represents a key regulatory point controlling cell survival and death.

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