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| Subject Categories: Proteins | Molecular Biology of Disease |
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| The EMBO Journal
(2002) 21, 2407–2417, doi: 10.1093/emboj/21.10.2407 |
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| Drug-induced ubiquitylation and degradation of ErbB receptor tyrosine kinases: implications for cancer therapy |
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| Ami Citri1, Iris Alroy1, Sara Lavi1, Chanan Rubin1, Wanping Xu2, Nicolas Grammatikakis3, Cam Patterson4, Len Neckers2, David W. Fry5 and Yosef Yarden1 |
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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 To whom correspondence should be addressed Yosef Yarden, yosef.yarden@weizmann.ac.il Received 3 September 2001; Revised 27 March 2002; Accepted 27 March 2002. |
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| Abstract |
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| 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. |
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| Keywords: geldanamycin, growth factor, protein kinase inhibitors, stress response, ubiquitin |
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