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

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.
Mesh Terms:
Antineoplastic Agents, Benzoquinones, Cell Division, Cell Line, Endocytosis, Enzyme Inhibitors, Humans, Lactams, Macrocyclic, Morpholines, Neoplasms, Protein-Tyrosine Kinases, Quinones, Receptor, erbB-2, Recombinant Proteins, Transfection, Ubiquitin
EMBO J.
Date: May. 15, 2002
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