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The endophilin-CIN85-Cbl complex mediates ligand-dependent downregulation of c-Met

Annalisa Petrelli1, Giorgio F Gilestro, Stefania Lanzardo

  • 1CNR-CIOS and Department of Genetics, Biology and Biochemistry, University of Torino, 10126 Torino, Italy.

Nature
|March 15, 2002
PubMed

Insights

A newly identified complex involving endophilins, CIN85, and Cbl regulates hepatocyte growth factor (HGF) receptor (Met) internalization. This discovery clarifies HGF receptor signaling and endocytosis mechanisms.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Signal Transduction

Background:

  • Tyrosine kinase receptor downregulation is crucial for signaling modulation.
  • Hepatocyte growth factor (HGF) receptor (Met) undergoes polyubiquitination and degradation upon ligand binding.
  • Mechanisms of HGF receptor endocytosis remain largely unknown.

Purpose of the Study:

  • To elucidate the molecular mechanisms governing HGF receptor (Met) endocytosis.
  • To identify the protein complex responsible for HGF receptor internalization.
  • To investigate the role of Cbl in HGF receptor signaling and endocytosis.

Main Methods:

  • Investigated the role of endophilins, CIN85, and Cbl in receptor endocytosis.
  • Utilized biochemical assays to demonstrate complex formation and binding interactions.
  • Assessed the impact of inhibiting complex formation on HGF receptor internalization and signaling.

Main Results:

  • A complex of endophilins, CIN85, and Cbl controls HGF receptor endocytosis.
  • Endophilins facilitate clathrin-coated vesicle formation and membrane invagination.
  • Cbl ubiquitinates activated HGF receptor and recruits the endophilin-CIN85 complex for internalization.
  • Inhibition of this complex blocks HGF receptor internalization and enhances signaling.

Conclusions:

  • Disclosed a novel mechanism for HGF receptor (Met) endocytosis involving endophilins, CIN85, and Cbl.
  • Established a functional link between Cbl, receptor signaling, and endocytosis.
  • Demonstrated that Cbl plays a critical role in regulating HGF receptor activity and biological responses.

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