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NLK-mediated phosphorylation of HDAC1 negatively regulates Wnt signaling

Masoumi, Katarzyna Chmielarska LU ; Daams, Renée LU ; Sime, Wondossen LU ; Siino, Valentina LU ; Ke, Hengning; Levander, Fredrik LU and Massoumi, Ramin LU (2017) In Molecular Biology of the Cell 28(2). p.346-355
Abstract

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... (More)

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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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Molecular Biology of the Cell
volume
28
issue
2
pages
10 pages
publisher
American Society for Cell Biology
external identifiers
  • scopus:85010676934
  • wos:000392493900012
ISSN
1059-1524
DOI
10.1091/mbc.E16-07-0547
language
English
LU publication?
yes
id
aeaa21dd-7ced-46c0-a80b-882a341d771e
date added to LUP
2017-02-28 11:45:41
date last changed
2018-10-31 17:56:51
@article{aeaa21dd-7ced-46c0-a80b-882a341d771e,
  abstract     = {<p>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.</p>},
  author       = {Masoumi, Katarzyna Chmielarska and Daams, Renée and Sime, Wondossen and Siino, Valentina and Ke, Hengning and Levander, Fredrik and Massoumi, Ramin},
  issn         = {1059-1524},
  language     = {eng},
  month        = {01},
  number       = {2},
  pages        = {346--355},
  publisher    = {American Society for Cell Biology},
  series       = {Molecular Biology of the Cell},
  title        = {NLK-mediated phosphorylation of HDAC1 negatively regulates Wnt signaling},
  url          = {http://dx.doi.org/10.1091/mbc.E16-07-0547},
  volume       = {28},
  year         = {2017},
}