• Register
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.


Leaving Community

Are you sure you want to leave this community? Leaving the community will revoke any permissions you have been granted in this community.


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