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.
(Less)
- author
- Masoumi, Katarzyna Chmielarska
LU
; Daams, Renée
LU
; Sime, Wondossen
LU
; Siino, Valentina
LU
; Ke, Hengning
; Levander, Fredrik
LU
and Massoumi, Ramin
LU
- organization
- publishing date
- 2017-01-15
- 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
- pmid:27903773
- 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
- 2025-01-07 08:40:06
@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}},
doi = {{10.1091/mbc.E16-07-0547}},
volume = {{28}},
year = {{2017}},
}