Geldanamycin abrogates ErbB2 association with proteasome-resistant beta-catenin in melanoma cells, increases beta-catenin-E-cadherin association, and decreases beta-catenin-sensitive transcription.
Beta-catenin undergoes both serine and tyrosine phosphorylation. Serine phosphorylation in the amino terminus targets beta-catenin for proteasome degradation, whereas tyrosine phosphorylation in the COOH terminus influences interaction with E-cadherin. We examined the tyrosine phosphorylation status of beta-catenin in melanoma cells expressing proteasome-resistant beta-catenin, as well as the effects that perturbation ... of beta-catenin tyrosine phosphorylation had on its association with E-cadherin and on its transcriptional activity. Beta-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 beta-catenin without perturbing either LAR or beta-catenin levels or LAR/beta-catenin association. Geldanamycin also stimulated tyrosine dephosphorylation of beta-catenin and increased beta-catenin/E-cadherin association, resulting in substantially decreased cell motility. Geldanamycin also decreased the nuclear beta-catenin level and inhibited beta-catenin-driven transcription, as assessed using two different beta-catenin-sensitive reporters and the endogenous cyclin D1 gene. These findings were confirmed by transient transfection of two beta-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 beta-catenin-ErbB2-binding domain. These data demonstrate that the functional activity of proteasome-resistant beta-catenin is regulated further by geldanamycin-sensitive tyrosine phosphorylation in melanoma cells.
Mesh Terms:
Antibiotics, Antineoplastic, Benzoquinones, Cadherins, Cell Movement, Cysteine Endopeptidases, Cysteine Proteinase Inhibitors, Cytoskeletal Proteins, Humans, Lactams, Macrocyclic, Melanoma, Multienzyme Complexes, Nerve Tissue Proteins, Phosphorylation, Point Mutation, Proteasome Endopeptidase Complex, Protein Tyrosine Phosphatases, Quinones, Receptor, erbB-2, Receptor-Like Protein Tyrosine Phosphatases, Class 2, Receptor-Like Protein Tyrosine Phosphatases, Class 4, Receptors, Cell Surface, Trans-Activators, Transcription, Genetic, Transcriptional Activation, Transfection, Tumor Cells, Cultured, Tyrosine, beta Catenin
Antibiotics, Antineoplastic, Benzoquinones, Cadherins, Cell Movement, Cysteine Endopeptidases, Cysteine Proteinase Inhibitors, Cytoskeletal Proteins, Humans, Lactams, Macrocyclic, Melanoma, Multienzyme Complexes, Nerve Tissue Proteins, Phosphorylation, Point Mutation, Proteasome Endopeptidase Complex, Protein Tyrosine Phosphatases, Quinones, Receptor, erbB-2, Receptor-Like Protein Tyrosine Phosphatases, Class 2, Receptor-Like Protein Tyrosine Phosphatases, Class 4, Receptors, Cell Surface, Trans-Activators, Transcription, Genetic, Transcriptional Activation, Transfection, Tumor Cells, Cultured, Tyrosine, beta Catenin
Cancer Res.
Date: Feb. 15, 2001
PubMed ID: 11245482
View in: Pubmed Google Scholar
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