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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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Rockefeller University Press
2018
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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. |
format | Online Article Text |
id | pubmed-6219716 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
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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