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Geldanamycin Abrogates ErbB2 Association with Proteasome-resistant ß-Catenin in Melanoma Cells, Increases ß-Catenin-E-Cadherin Association, and Decreases ß-Catenin-sensitive Transcription

Department of Cell and Cancer Biology, Medicine Branch, National Cancer Institute, Rockville, Maryland 20850 [P. B., W. G. A., P. N., J. T., L. M. N.]; Oncology and Hematology Branch, Clinic of Pediatrics, University of Padova, Padova 35128, Italy [P. B., A. R.]; Institut Municipal d’Investigacio Medica, Universitat Pompeu Fabra, Barcelona 08003, Spain [G. H.]; and Departament de Bioquimica i Biologia Molecular, Universitat Autonoma de Barcelona, Bellaterra 08193, Spain [M. D.]

ß-catenin undergoes both serine and tyrosine phosphorylation. Serine phosphorylation in the amino terminus targets ß-catenin for proteasome degradation, whereas tyrosine phosphorylation in the COOH terminus influences interaction with E-cadherin. We examined the tyrosine phosphorylation status of ß-catenin in melanoma cells expressing proteasome-resistant ß-catenin, as well as the effects that perturbation of ß-catenin tyrosine phosphorylation had on its association with E-cadherin and on its transcriptional activity. ß-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 ß-catenin without perturbing either LAR or ß-catenin levels or LAR/ß-catenin association. Geldanamycin also stimulated tyrosine dephosphorylation of ß-catenin and increased ß-catenin/E-cadherin association, resulting in substantially decreased cell motility. Geldanamycin also decreased the nuclear ß-catenin level and inhibited ß-catenin-driven transcription, as assessed using two different ß-catenin-sensitive reporters and the endogenous cyclin D1 gene. These findings were confirmed by transient transfection of two ß-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 ß-catenin-ErbB2-binding domain. These data demonstrate that the functional activity of proteasome-resistant ß-catenin is regulated further by geldanamycin-sensitive tyrosine phosphorylation in melanoma cells.

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