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β-Catenin is a pH sensor with decreased stability at higher intracellular pH

β-Catenin functions as an adherens junction protein for cell–cell adhesion and as a signaling protein. β-catenin function is dependent on its stability, which is regulated by protein–protein interactions that stabilize β-catenin or target it for proteasome-mediated degradation. In this study, we sho...

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Autores principales: White, Katharine A., Grillo-Hill, Bree K., Esquivel, Mario, Peralta, Jobelle, Bui, Vivian N., Chire, Ismahan, Barber, Diane L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6219716/
https://www.ncbi.nlm.nih.gov/pubmed/30315137
http://dx.doi.org/10.1083/jcb.201712041
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author White, Katharine A.
Grillo-Hill, Bree K.
Esquivel, Mario
Peralta, Jobelle
Bui, Vivian N.
Chire, Ismahan
Barber, Diane L.
author_facet White, Katharine A.
Grillo-Hill, Bree K.
Esquivel, Mario
Peralta, Jobelle
Bui, Vivian N.
Chire, Ismahan
Barber, Diane L.
author_sort White, Katharine A.
collection PubMed
description β-Catenin functions as an adherens junction protein for cell–cell adhesion and as a signaling protein. β-catenin function is dependent on its stability, which is regulated by protein–protein interactions that stabilize β-catenin or target it for proteasome-mediated degradation. In this study, we show that β-catenin stability is regulated by intracellular pH (pHi) dynamics, with decreased stability at higher pHi in both mammalian cells and Drosophila melanogaster. β-Catenin degradation requires phosphorylation of N-terminal residues for recognition by the E3 ligase β-TrCP. While β-catenin phosphorylation was pH independent, higher pHi induced increased β-TrCP binding and decreased β-catenin stability. An evolutionarily conserved histidine in β-catenin (found in the β-TrCP DSGIHS destruction motif) is required for pH-dependent binding to β-TrCP. Expressing a cancer-associated H36R–β-catenin mutant in the Drosophila eye was sufficient to induce Wnt signaling and produced pronounced tumors not seen with other oncogenic β-catenin alleles. We identify pHi dynamics as a previously unrecognized regulator of β-catenin stability, functioning in coincidence with phosphorylation.
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spelling pubmed-62197162019-05-05 β-Catenin is a pH sensor with decreased stability at higher intracellular pH White, Katharine A. Grillo-Hill, Bree K. Esquivel, Mario Peralta, Jobelle Bui, Vivian N. Chire, Ismahan Barber, Diane L. J Cell Biol Research Articles β-Catenin functions as an adherens junction protein for cell–cell adhesion and as a signaling protein. β-catenin function is dependent on its stability, which is regulated by protein–protein interactions that stabilize β-catenin or target it for proteasome-mediated degradation. In this study, we show that β-catenin stability is regulated by intracellular pH (pHi) dynamics, with decreased stability at higher pHi in both mammalian cells and Drosophila melanogaster. β-Catenin degradation requires phosphorylation of N-terminal residues for recognition by the E3 ligase β-TrCP. While β-catenin phosphorylation was pH independent, higher pHi induced increased β-TrCP binding and decreased β-catenin stability. An evolutionarily conserved histidine in β-catenin (found in the β-TrCP DSGIHS destruction motif) is required for pH-dependent binding to β-TrCP. Expressing a cancer-associated H36R–β-catenin mutant in the Drosophila eye was sufficient to induce Wnt signaling and produced pronounced tumors not seen with other oncogenic β-catenin alleles. We identify pHi dynamics as a previously unrecognized regulator of β-catenin stability, functioning in coincidence with phosphorylation. Rockefeller University Press 2018-11-05 /pmc/articles/PMC6219716/ /pubmed/30315137 http://dx.doi.org/10.1083/jcb.201712041 Text en © 2018 White et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
spellingShingle Research Articles
White, Katharine A.
Grillo-Hill, Bree K.
Esquivel, Mario
Peralta, Jobelle
Bui, Vivian N.
Chire, Ismahan
Barber, Diane L.
β-Catenin is a pH sensor with decreased stability at higher intracellular pH
title β-Catenin is a pH sensor with decreased stability at higher intracellular pH
title_full β-Catenin is a pH sensor with decreased stability at higher intracellular pH
title_fullStr β-Catenin is a pH sensor with decreased stability at higher intracellular pH
title_full_unstemmed β-Catenin is a pH sensor with decreased stability at higher intracellular pH
title_short β-Catenin is a pH sensor with decreased stability at higher intracellular pH
title_sort β-catenin is a ph sensor with decreased stability at higher intracellular ph
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6219716/
https://www.ncbi.nlm.nih.gov/pubmed/30315137
http://dx.doi.org/10.1083/jcb.201712041
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