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

The Cbl family of ubiquitin ligases in mammals contains three members, Cbl, Cbl-b, and Cbl-3, that are involved in down-regulation of receptor tyrosine kinases (RTKs) by mediating receptor ubiquitination and degradation. More recently, a novel pathway has been identified whereby Cbl promotes internalization of EGF receptor via a CIN85/endophilin pathway that is functionally separable from the ubiquitin ligase activity of Cbl (1). Here we show that Cbl-b, but not Cbl-3, utilize the same mechanism to down-regulate multiple RTKs. CIN85 was shown to bind to the minimal binding domain identified in the carboxyl terminus of Cbl-b. Ligand-induced phosphorylation of Cbl-b further increased their interactions and led to a rapid and sustained recruitment of CIN85 in the complex with EGF or PDGF receptors. Inhibition of binding between CIN85 and Cbl-b was sufficient to impair Cbl-b-mediated internalization of EGF receptors, while being dispensable for Cbl-b-directed polyubiquitination of EGF receptors. Moreover, CIN85 and Cbl/Cbl-b were constitutively associated with activated PDGF, EGF, or c-Kit receptors in several tumor cell lines. Our data reveal a common pathway utilized by Cbl and Cbl-b that may have an important and redundant function in negative regulation of ligand-activated as well as oncogenically activated RTKs in vivo.

Pubmed ID: 12177062


  • Szymkiewicz I
  • Kowanetz K
  • Soubeyran P
  • Dinarina A
  • Lipkowitz S
  • Dikic I


The Journal of biological chemistry

Publication Data

October 18, 2002

Associated Grants


Mesh Terms

  • 3T3 Cells
  • Adaptor Proteins, Signal Transducing
  • Animals
  • CHO Cells
  • Carrier Proteins
  • Cell Line
  • Cell Line, Transformed
  • Cloning, Molecular
  • Cricetinae
  • Down-Regulation
  • Endocytosis
  • Epidermal Growth Factor
  • HeLa Cells
  • Humans
  • Ligands
  • Mice
  • Microscopy, Fluorescence
  • Models, Biological
  • Phosphoproteins
  • Phosphorylation
  • Platelet-Derived Growth Factor
  • Precipitin Tests
  • Protein Binding
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-cbl
  • Proto-Oncogene Proteins c-kit
  • Receptor Protein-Tyrosine Kinases
  • Time Factors
  • Transfection
  • Two-Hybrid System Techniques
  • Ubiquitin-Protein Ligases