EMBO J 2002,
PMID: 12006493
Citri, Ami; Alroy, Iris; Lavi, Sara; Rubin, Chanan; Xu, Wanping; Grammatikakis, Nicolas; Patterson, Cam; Neckers, Len; Fry, David W; Yarden, Yosef
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.
Diseases/Pathways annotated by Medline MESH: Neoplasms
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Text Mining Data
Dashed line = No text mining data
Manually curated Databases
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IRef Biogrid Interaction:
EGFR
—
HSP90AA1
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
HSPA4
—
ERBB2
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
UBC
—
ERBB2
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
HSPA4
—
EGFR
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
EGFR
—
UBC
(physical association, affinity chromatography technology)
-
IRef Biogrid Interaction:
ERBB2
—
HSP90AA1
(physical association, affinity chromatography technology)
In total, 6 gene pairs are associated to this article in curated databases