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NLK-mediated phosphorylation of HDAC1 negatively regulates Wnt signaling

The Wnt signaling pathway is essential in regulating various cellular processes. Different mechanisms of inhibition for Wnt signaling have been proposed. Besides β-catenin degradation through the proteasome, nemo-like kinase (NLK) is another molecule that is known to negatively regulate Wnt signalin...

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Autores principales: Masoumi, Katarzyna Chmielarska, Daams, Renée, Sime, Wondossen, Siino, Valentina, Ke, Hengning, Levander, Fredrik, Massoumi, Ramin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5231902/
https://www.ncbi.nlm.nih.gov/pubmed/27903773
http://dx.doi.org/10.1091/mbc.E16-07-0547
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author Masoumi, Katarzyna Chmielarska
Daams, Renée
Sime, Wondossen
Siino, Valentina
Ke, Hengning
Levander, Fredrik
Massoumi, Ramin
author_facet Masoumi, Katarzyna Chmielarska
Daams, Renée
Sime, Wondossen
Siino, Valentina
Ke, Hengning
Levander, Fredrik
Massoumi, Ramin
author_sort Masoumi, Katarzyna Chmielarska
collection PubMed
description The Wnt signaling pathway is essential in regulating various cellular processes. Different mechanisms of inhibition for Wnt signaling have been proposed. Besides β-catenin degradation through the proteasome, nemo-like kinase (NLK) is another molecule that is known to negatively regulate Wnt signaling. However, the mechanism by which NLK mediates the inhibition of Wnt signaling was not known. In the present study, we used primary embryonic fibroblast cells isolated from NLK-deficient mice and showed that these cells proliferate faster and have a shorter cell cycle than wild-type cells. In NLK-knockout cells, we observed sustained interaction between Lef1 and β-catenin, leading to elevated luciferase reporter of β-catenin/Lef1–mediated transcriptional activation. The mechanism for the reduced β-catenin/Lef1 promoter activation was explained by phosphorylation of HDAC1 at serine 421 via NLK. The phosphorylation of HDAC1 was achieved only in the presence of wild-type NLK because a catalytically inactive mutant of NLK was unable to phosphorylate HDAC1 and reduced the luciferase reporter of β-catenin/Lef1–mediated transcriptional activation. This result suggests that NLK and HDAC1 together negatively regulate Wnt signaling, which is vital in preventing aberrant proliferation of nontransformed primary fibroblast cells.
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spelling pubmed-52319022017-03-30 NLK-mediated phosphorylation of HDAC1 negatively regulates Wnt signaling Masoumi, Katarzyna Chmielarska Daams, Renée Sime, Wondossen Siino, Valentina Ke, Hengning Levander, Fredrik Massoumi, Ramin Mol Biol Cell Articles The Wnt signaling pathway is essential in regulating various cellular processes. Different mechanisms of inhibition for Wnt signaling have been proposed. Besides β-catenin degradation through the proteasome, nemo-like kinase (NLK) is another molecule that is known to negatively regulate Wnt signaling. However, the mechanism by which NLK mediates the inhibition of Wnt signaling was not known. In the present study, we used primary embryonic fibroblast cells isolated from NLK-deficient mice and showed that these cells proliferate faster and have a shorter cell cycle than wild-type cells. In NLK-knockout cells, we observed sustained interaction between Lef1 and β-catenin, leading to elevated luciferase reporter of β-catenin/Lef1–mediated transcriptional activation. The mechanism for the reduced β-catenin/Lef1 promoter activation was explained by phosphorylation of HDAC1 at serine 421 via NLK. The phosphorylation of HDAC1 was achieved only in the presence of wild-type NLK because a catalytically inactive mutant of NLK was unable to phosphorylate HDAC1 and reduced the luciferase reporter of β-catenin/Lef1–mediated transcriptional activation. This result suggests that NLK and HDAC1 together negatively regulate Wnt signaling, which is vital in preventing aberrant proliferation of nontransformed primary fibroblast cells. The American Society for Cell Biology 2017-01-15 /pmc/articles/PMC5231902/ /pubmed/27903773 http://dx.doi.org/10.1091/mbc.E16-07-0547 Text en © 2017 Masoumi et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology.
spellingShingle Articles
Masoumi, Katarzyna Chmielarska
Daams, Renée
Sime, Wondossen
Siino, Valentina
Ke, Hengning
Levander, Fredrik
Massoumi, Ramin
NLK-mediated phosphorylation of HDAC1 negatively regulates Wnt signaling
title NLK-mediated phosphorylation of HDAC1 negatively regulates Wnt signaling
title_full NLK-mediated phosphorylation of HDAC1 negatively regulates Wnt signaling
title_fullStr NLK-mediated phosphorylation of HDAC1 negatively regulates Wnt signaling
title_full_unstemmed NLK-mediated phosphorylation of HDAC1 negatively regulates Wnt signaling
title_short NLK-mediated phosphorylation of HDAC1 negatively regulates Wnt signaling
title_sort nlk-mediated phosphorylation of hdac1 negatively regulates wnt signaling
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5231902/
https://www.ncbi.nlm.nih.gov/pubmed/27903773
http://dx.doi.org/10.1091/mbc.E16-07-0547
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