Drug-induced ubiquitylation and degradation of ErbB receptor tyrosine kinases: Implications for cancer therapy

Ami Citri, Iris Alroy, Sara Lavi, Chanan Rubin, Wanping Xu, Nicolas Grammatikakis, Cam Patterson, Len Neckers, David W. Fry, Yosef Yarden

Research output: Contribution to journalArticlepeer-review

210 Scopus citations

Abstract

Overexpression of ErbB-2/HER2 is associated with aggressive human malignancies, and therapeutic strategies targeting the oncoprotein are currently in different stages of clinical application. Tyrosine kinase inhibitors (TKIs) that block the nucleotide-binding site of the kinase are especially effective against tumors. Here we report an unexpected activity of TKIs: Along with inhibition of tyrosine phosphorylation, they enhance ubiquitylation and accelerate endocytosis and subsequent intracellular destruction of ErbB-2 molecules. Especially potent is an irreversible TKI (CI-1033) that alkylates a cysteine specific to ErbB receptors. The degradative pathway stimulated by TKIs appears to be chaperone mediated, and is common to the heat shock protein 90 (Hsp90) antagonist geldanamycin and a stress-induced mechanism. In agreement with this conclusion, CI-1033 and geldanamycin additively inhibit tumor cell growth. Based upon a model for drug-induced degradation of ErbB-2, we propose a general strategy for selective destruction of oncoproteins by targeting their interaction with molecular chaperones.

Original languageAmerican English
Pages (from-to)2407-2417
Number of pages11
JournalEMBO Journal
Volume21
Issue number10
DOIs
StatePublished - 15 May 2002
Externally publishedYes

Keywords

  • Geldanamycin
  • Growth factor
  • Protein kinase inhibitors
  • Stress response
  • Ubiquitin

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