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  • The EMBO Journal (2002) 21, 2407 - 2417
  • doi:10.1093/emboj/21.10.2407

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

Ami Citri1, Iris Alroy1, Sara Lavi1, Chanan Rubin1, Wanping Xu2, Nicolas Grammatikakis3, Cam Patterson4, Len Neckers2, David W. Fry5 and Yosef Yarden1

  1. Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel
  2. Medicine Branch, National Cancer Institute, Rockville, MD 20850 USA
  3. Department of Microbiology and Immunology, Queen's University, Kingston, Ontario, Canada, K7L 3N6
  4. Program in Molecular Cardiology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
  5. Department of Cancer Research, Pfizer Global Research and Development, Ann Arbor, MI 48106, USA

Correspondence to:

Yosef Yarden, E-mail: yosef.yarden@weizmann.ac.il

Received 3 September 2001; Accepted 27 March 2002; Revised 27 March 2002

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.

  • Keywords:

    • geldanamycin,
    • growth factor,
    • protein kinase inhibitors,
    • stress response,
    • ubiquitin