Association with HSP90 inhibits Cbl-mediated down-regulation of mutant epidermal growth factor receptors Academic Article uri icon


MeSH Major

  • HSP90 Heat-Shock Proteins
  • Oncogene Protein v-cbl
  • Receptor, Epidermal Growth Factor


  • Activating mutations in the epidermal growth factor receptor (EGFR), localized in the activation loop within the kinase domain, have been discovered in non-small cell lung cancers (NSCLC). Most of these mutants are exquisitely sensitive to EGFR tyrosine kinase inhibitors, suggesting that they generate receptor dependence in the cancers that express them. 32D cells stably expressing EGFR-L861Q and EGFR-L858R but not wild-type EGFR exhibited ligand-independent receptor phosphorylation and viability. Ligand-induced receptor down-regulation (LIRD) was impaired in mutant-expressing cells. The EGFR mutants were constitutively associated with the E3 ubiquitin ligase Cbl but did not associate with the adaptor protein CIN85 on the addition of ligand. Inhibition of HSP90 activity with geldanamycin restored Cbl function as indicated by receptor ubiquitination and LIRD. These results suggest that EGFR mutants form defective endocytic complexes. In addition, HSP90 plays a role in maintaining the functional conformation of EGFR mutants and protecting activated receptors from LIRD.

publication date

  • July 15, 2006



  • Academic Article



  • eng

Digital Object Identifier (DOI)

  • 10.1158/0008-5472.CAN-06-1042

PubMed ID

  • 16849543

Additional Document Info

start page

  • 6990

end page

  • 7


  • 66


  • 14