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SorLA and CLC:CLF-1-dependent Downregulation of CNTFRα as Demonstrated by Western Blotting, Inhibition of Lysosomal Enzymes, and Immunocytochemistry
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Cbl-CIN85-endophilin complex mediates ligand-induced downregulation of EGF receptors

Philippe Soubeyran1, Katarzyna Kowanetz, Iwona Szymkiewicz

  • 1Ludwig Institute for Cancer Research, Box 595, Husargatan 3, Uppsala, S-75124, Sweden.

Nature
|March 15, 2002
PubMed

Insights

The Cbl protein regulates epidermal growth factor (EGF) receptor internalization via binding to CIN85 and endophilins. This process is separate from Cbl

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Signal Transduction

Background:

  • Cbl is a multi-adaptor protein crucial for downregulating receptor tyrosine kinases.
  • Cbl-mediated ubiquitination is essential for receptor degradation and signal transduction cessation.

Purpose of the Study:

  • To investigate the role of Cbl in epidermal growth factor (EGF) receptor endocytosis.
  • To elucidate the mechanism by which Cbl regulates EGF receptor internalization.

Main Methods:

  • Investigated the interaction between Cbl, CIN85, and endophilins.
  • Utilized EGF stimulation to observe complex formation and receptor trafficking.
  • Assessed the impact of inhibiting Cbl-CIN85 interactions on EGF receptor internalization and degradation.

Main Results:

  • Cbl recruits CIN85 and endophilins to activated EGF receptors, controlling internalization.
  • CIN85 constitutively binds endophilins, with increased binding to Cbl upon EGF stimulation.
  • Inhibiting these interactions blocked EGF receptor internalization and delayed degradation, enhancing gene transcription.

Conclusions:

  • Cbl regulates EGF receptor endocytosis through a mechanism involving CIN85 and endophilins.
  • This endocytic regulation is functionally distinct from Cbl's ubiquitin ligase activity.
  • The C-terminal region of Cbl mediates ligand-dependent receptor tyrosine kinase downregulation via a novel pathway.

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