title: NLK-mediated phosphorylation of HDAC1 negatively regulates Wnt signaling.
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 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.
authors.affiliation: Department of Laboratory Medicine, Translational Cancer Research, Lund University, Lund 22381, Sweden.
authors.forename: Katarzyna Chmielarska
authors.initials: KC
authors.lastname: Masoumi
authors.affiliation: Department of Laboratory Medicine, Translational Cancer Research, Lund University, Lund 22381, Sweden.
authors.forename: Renée
authors.initials: R
authors.lastname: Daams
authors.affiliation: Department of Laboratory Medicine, Translational Cancer Research, Lund University, Lund 22381, Sweden.
authors.forename: Wondossen
authors.initials: W
authors.lastname: Sime
authors.affiliation: Department of Immunotechnology, Lund University, Lund 22381, Sweden.
authors.forename: Valentina
authors.initials: V
authors.lastname: Siino
authors.affiliation: Department of Laboratory Medicine, Translational Cancer Research, Lund University, Lund 22381, Sweden.|Cancer Research Institute, General Hospital, Ningxia Medical University, Yinchuan 750004, China.
authors.forename: Hengning
authors.initials: H
authors.lastname: Ke
authors.affiliation: Department of Immunotechnology, Lund University, Lund 22381, Sweden.|National Bioinformatics Infrastructure Sweden, Department of Immunotechnology, Lund University, Lund 22381, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Levander
authors.affiliation: Department of Laboratory Medicine, Translational Cancer Research, Lund University, Lund 22381, Sweden Ramin.Massoumi@med.lu.se.
authors.forename: Ramin
authors.initials: R
authors.lastname: Massoumi
mesh_terms: D000818:Animals; D002453:Cell Cycle; D005347:Fibroblasts; D056284:Histone Deacetylase 1 / Q000378:metabolism* / Q000502:physiology; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism* / Q000502:physiology; D010766:Phosphorylation; D061251:Primary Cell Culture; D017346:Protein Serine-Threonine Kinases; D015398:Signal Transduction / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism
chemical_list: C497574:Lef1 protein, mouse; D051821:Lymphoid Enhancer-Binding Factor 1; D015534:Trans-Activators; D014157:Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin; C408347:Nlk protein, mouse; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C484389:Hdac1 protein, mouse; D056284:Histone Deacetylase 1