Cargando…
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...
Autores principales: | , , , , , , |
---|---|
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 |
_version_ | 1782494577296408576 |
---|---|
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. |
format | Online Article Text |
id | pubmed-5231902 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT masoumikatarzynachmielarska nlkmediatedphosphorylationofhdac1negativelyregulateswntsignaling AT daamsrenee nlkmediatedphosphorylationofhdac1negativelyregulateswntsignaling AT simewondossen nlkmediatedphosphorylationofhdac1negativelyregulateswntsignaling AT siinovalentina nlkmediatedphosphorylationofhdac1negativelyregulateswntsignaling AT kehengning nlkmediatedphosphorylationofhdac1negativelyregulateswntsignaling AT levanderfredrik nlkmediatedphosphorylationofhdac1negativelyregulateswntsignaling AT massoumiramin nlkmediatedphosphorylationofhdac1negativelyregulateswntsignaling |