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CIN85 participates in Cbl-b-mediated down-regulation of receptor tyrosine kinases

Iwona Szymkiewicz1, Katarzyna Kowanetz, Philippe Soubeyran

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

The Journal of Biological Chemistry
|August 15, 2002
PubMed

Insights

The Cbl-b protein regulates receptor tyrosine kinases (RTKs) through a pathway involving CIN85, distinct from its ubiquitin ligase activity. This mechanism is crucial for down-regulating RTKs in both normal and cancer cells.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • The Cbl family of ubiquitin ligases (Cbl, Cbl-b, Cbl-3) regulates receptor tyrosine kinases (RTKs) via ubiquitination and degradation.
  • A novel Cbl-mediated pathway involving CIN85/endophilin facilitates EGF receptor internalization, separate from its ligase function.

Purpose of the Study:

  • To investigate if Cbl-b utilizes the CIN85/endophilin pathway for RTK down-regulation.
  • To elucidate the role of CIN85 in Cbl-b-mediated receptor internalization and RTK regulation.

Main Methods:

  • Investigated Cbl-b interactions with CIN85 using binding assays.
  • Analyzed the effect of CIN85-Cbl-b binding inhibition on EGF receptor internalization.
  • Examined the association of CIN85, Cbl/Cbl-b with activated RTKs in tumor cell lines.

Main Results:

  • Cbl-b, but not Cbl-3, uses the CIN85/endophilin pathway to down-regulate multiple RTKs.
  • CIN85 binds to Cbl-b's carboxyl terminus; phosphorylation enhances this interaction.
  • Inhibiting CIN85-Cbl-b binding impairs Cbl-b-mediated EGF receptor internalization but not ubiquitination.
  • CIN85 and Cbl/Cbl-b associate with activated PDGF, EGF, and c-Kit receptors in tumor cells.

Conclusions:

  • Cbl-b employs a common pathway with Cbl for RTK internalization via CIN85.
  • This pathway plays a significant and potentially redundant role in negatively regulating activated RTKs in vivo.

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