Geldanamycin abrogates ErbB2 association with proteasome-resistant β-catenin in melanoma cells, increases β-catenin-E-cadherin association, and decreases β-catenin-sensitive transcription

Paolo Bonvini, Won G. An, Angelo Rosolen, Phongmai Nguyen, Jane Trepel, Antonio Garcia De Herreros, Mireia Dunach, Leonard M. Neckers

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79 Citations (Scopus)

Abstract

β-catenin undergoes both serine and tyrosine phosphorylation. Serine phosphorylation in the amino terminus targets β-catenin for proteasome degradation, whereas tyrosine phosphorylation in the COOH terminus influences interaction with E-cadherin. We examined the tyrosine phosphorylation status of β-catenin in melanoma cells expressing proteasome-resistant β-catenin, as well as the effects that perturbation of β-catenin tyrosine phosphorylation had on its association with E-cadherin and on its transcriptional activity. β-catenin is tyrosine phosphorylated in three melanoma cell lines and associates with both the ErbB2 receptor tyrosine kinase and the LAR receptor tyrosine phosphatase. Geldanamycin, a drug which destabilizes ErbB2, caused rapid cellular depletion of the kinase and loss of its association with β-catenin without perturbing either LAR or β-catenin levels or LAR/β-catenin association. Geldanamycin also stimulated tyrosine dephosphorylation of β-catenin and increased β-catenin/E-cadherin association, resulting in substantially decreased cell motility. Geldanamycin also decreased the nuclear β-catenin level and inhibited β-catenin-driven transcription, as assessed using two different β-catenin-sensitive reporters and the endogenous cyclin D1 gene. These findings were confirmed by transient transfection of two β-catenin point mutants, Tyr-654Phe and Tyr-654Glu, which, respectively, mimic the dephosphorylated and phosphorylated states of Tyr-654, a tyrosine residue contained within the β-catenin-ErbB2-binding domain. These data demonstrate that the functional activity of proteasome-resistant β-catenin is regulated further by geldanamycin-sensitive tyrosine phosphorylation in melanoma cells.
Original languageEnglish
Pages (from-to)1671-1677
JournalCancer Research
Volume61
Issue number4
Publication statusPublished - 15 Feb 2001

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