Association with HSP90 inhibits Cbl-mediated down-regulation of mutant epidermal growth factor receptors Journal Article
| Authors: | Yang, S.; Qu, S.; Perez-Tores, M.; Sawai, A.; Rosen, N.; Solit, D. B.; Arteaga, C. L. |
| Article Title: | Association with HSP90 inhibits Cbl-mediated down-regulation of mutant epidermal growth factor receptors |
| Abstract: | 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. ©2006 American Association for Cancer Research. |
| Keywords: | controlled study; protein phosphorylation; human cell; mutation; erlotinib; nonhuman; mutant protein; ubiquitin; animal cell; mouse; animals; mice; cell survival; protein degradation; lung non small cell cancer; lung neoplasms; epidermal growth factor receptor; animal experiment; animal model; down-regulation; receptor, epidermal growth factor; drug effect; transfection; wild type; cetuximab; mice, inbred balb c; gene expression regulation, neoplastic; ubiquitination; gefitinib; transplantation, heterologous; heat shock protein 90; hsp90 heat-shock proteins; ligands; down regulation; cbl protein; ubiquitin protein ligase e3; phosphotransferase; epidermal growth factor receptor kinase inhibitor; transforming growth factor alpha; geldanamycin; adaptor protein; receptor down regulation; oncogene protein v-cbl |
| Journal Title: | Cancer Research |
| Volume: | 66 |
| Issue: | 14 |
| ISSN: | 0008-5472 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2006-07-15 |
| Start Page: | 6990 |
| End Page: | 6997 |
| Language: | English |
| DOI: | 10.1158/0008-5472.can-06-1042 |
| PUBMED: | 16849543 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 38" - "Export Date: 4 June 2012" - "CODEN: CNREA" - "Source: Scopus" |
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