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Drug‐induced ubiquitylation and degradation of ErbB receptor tyrosine kinases: implications for cancer therapy
Author(s) -
Citri Ami,
Alroy Iris,
Lavi Sara,
Rubin Chanan,
Xu Wanping,
Grammatikakis Nicolas,
Patterson Cam,
Neckers Len,
Fry David W.,
Yarden Yosef
Publication year - 2002
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1093/emboj/21.10.2407
Subject(s) - geldanamycin , hsp90 , erbb , biology , tyrosine kinase , receptor tyrosine kinase , cancer research , kinase , phosphorylation , heat shock protein , tyrosine kinase inhibitor , microbiology and biotechnology , signal transduction , biochemistry , cancer , genetics , gene
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.