scholarly journals WNK regulates Wnt signalling and β-Catenin levels by interfering with the interaction between β-Catenin and GID

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Atsushi Sato ◽  
Masahiro Shimizu ◽  
Toshiyasu Goto ◽  
Hiroyuki Masuno ◽  
Hiroyuki Kagechika ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Therapeutic Target ◽  
E3 Ubiquitin Ligase ◽  
Wnt Signalling ◽  
Signalling Pathway ◽  
Tumour Development ◽  
Wnt Signalling Pathway

Abstractβ-Catenin is an important component of the Wnt signalling pathway. As dysregulation or mutation of this pathway causes many diseases, including cancer, the β-Catenin level is carefully regulated by the destruction complex in the Wnt signalling pathway. However, the mechanisms underlying the regulation of β-Catenin ubiquitination and degradation remain unclear. Here, we find that WNK (With No Lysine [K]) kinase is a potential regulator of the Wnt signalling pathway. We show that WNK protects the interaction between β-Catenin and the Glucose-Induced degradation Deficient (GID) complex, which includes an E3 ubiquitin ligase targeting β-Catenin, and that WNK regulates the β-Catenin level. Furthermore, we show that WNK inhibitors induced β-Catenin degradation and that one of these inhibitors suppressed xenograft tumour development in mice. These results suggest that WNK is a previously unrecognized regulator of β-Catenin and a therapeutic target of cancer.

MAP3K1 functionally interacts with Axin1 in the canonical Wnt signalling pathway

2010 ◽  
Vol 391 (2/3) ◽  
Author(s):  
Ser Sue Ng ◽  
Tokameh Mahmoudi ◽  
Vivian S.W. Li ◽  
Pantelis Hatzis ◽  
Paul J. Boersema ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Target Genes ◽  
Wnt Signalling ◽  
Signalling Pathway ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Endogenous Gene ◽  
Wnt Signalling Pathway ◽  
Mitogen Activated Protein ◽  
Canonical Wnt

Abstract A central point of regulation in the Wnt/β-catenin signalling pathway is the formation of the β-catenin destruction complex. Axin1, an essential negative regulator of Wnt signalling, serves as a scaffold within this complex and is critical for rapid turnover of β-catenin. To examine the mechanism by which Wnt signalling disables the destruction complex, we used an immunoprecipitation-coupled proteomics approach to identify novel endogenous binding partners of Axin1. We found mitogen-activated protein kinase kinase kinase 1 (MAP3K1) as an Axin1 interactor in Ls174T colorectal cancer (CRC) cells. Importantly, confirmation of this interaction in HEK293T cells indicated that the Axin1-MAP3K1 interaction is induced and modulated by Wnt stimulation. siRNA depletion of MAP3K1 specifically abrogated TCF/LEF-driven transcription and Wnt3A-driven endogenous gene expression in both HEK293T as well as DLD-1 CRC. Expression of ubiquitin ligase mutants of MAP3K1 abrogated TCF/LEF transcription, whereas kinase mutants had no effect in TCF-driven activity, highlighting the essential role of the MAP3K1 E3 ubiquitin ligase activity in regulation of the Wnt/β-catenin pathway. These results suggest that MAP3K1, previously reported as an Axin1 inter-actor in c-Jun NH2-terminal kinase pathway, is also involved in the canonical Wnt signalling pathway and positively regulates expression of Wnt target genes.

GSK3 takes centre stage more than 20 years after its discovery

2001 ◽  
Vol 359 (1) ◽  
pp. 1-16 ◽  
Author(s):  
Sheelagh FRAME ◽  
Philip COHEN
Keyword(s):  
Substrate Specificity ◽  
Therapeutic Potential ◽  
Glycogen Synthase ◽  
Glycogen Metabolism ◽  
Wnt Signalling ◽  
Signalling Pathway ◽  
Dimensional Structure ◽  
Entire Body ◽  
Wnt Signalling Pathway ◽  
Wnt Proteins

Identified originally as a regulator of glycogen metabolism, glycogen synthase kinase-3 (GSK3) is now a well-established component of the Wnt signalling pathway, which is essential for setting up the entire body pattern during embryonic development. It may also play important roles in protein synthesis, cell proliferation, cell differentiation, microtubule dynamics and cell motility by phosphorylating initiation factors, components of the cell-division cycle, transcription factors and proteins involved in microtubule function and cell adhesion. Generation of the mouse knockout of GSK3β, as well as studies in neurons, also suggest an important role in apoptosis. The substrate specificity of GSK3 is unusual in that efficient phosphorylation of many of its substrates requires the presence of another phosphorylated residue optimally located four amino acids C-terminal to the site of GSK3 phosphorylation. Recent experiments, including the elucidation of its three-dimensional structure, have enhanced our understanding of the molecular basis for the unique substrate specificity of GSK3. Insulin and growth factors inhibit GSK3 by triggering its phosphorylation, turning the N-terminus into a pseudosubstrate inhibitor that competes for binding with the ‘priming phosphate’ of substrates. In contrast, Wnt proteins inhibit GSK3 in a completely different way, by disrupting a multiprotein complex comprising GSK3 and its substrates in the Wnt signalling pathway, which do not appear to require a ‘priming phosphate’. These latest findings have generated an enormous amount of interest in the development of drugs that inhibit GSK3 and which may have therapeutic potential for the treatment of diabetes, stroke and Alzheimer's disease.

scholarly journals Wnt-signalling pathway in ovarian epithelial tumours: increased expression of β-catenin and GSK3β

2003 ◽  
Vol 89 (7) ◽  
pp. 1298-1304 ◽  
Author(s):  
K Rask ◽  
A Nilsson ◽  
M Brännström ◽  
P Carlsson ◽  
P Hellberg ◽  
...  
Keyword(s):  
Wnt Signalling ◽  
Signalling Pathway ◽  
Wnt Signalling Pathway ◽  
Epithelial Tumours

scholarly journals Epigenetic regulation of DACT2, a key component of the Wnt signalling pathway in human lung cancer

2013 ◽  
Vol 230 (2) ◽  
pp. 194-204 ◽  
Author(s):  
Yan Jia ◽  
Yunsheng Yang ◽  
Malcolm V Brock ◽  
Qimin Zhan ◽  
James G Herman ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Epigenetic Regulation ◽  
Human Lung ◽  
Wnt Signalling ◽  
Signalling Pathway ◽  
Human Lung Cancer ◽  
Wnt Signalling Pathway

scholarly journals Is resistant starch protective against colorectal cancer via modulation of the WNT signalling pathway?

2015 ◽  
Vol 74 (3) ◽  
pp. 282-291 ◽  
Author(s):  
Fiona C. Malcomson ◽  
Naomi D. Willis ◽  
John C. Mathers
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Resistant Starch ◽  
Wnt Pathway ◽  
Wnt Signalling ◽  
Signalling Pathway ◽  
Wnt Signalling Pathway ◽  
Crypt Cell Proliferation ◽  
And Migration ◽  
Epigenetic Modulation

Epidemiological and experimental evidence suggests that non-digestible carbohydrates (NDC) including resistant starch are protective against colorectal cancer. These anti-neoplastic effects are presumed to result from the production of the SCFA, butyrate, by colonic fermentation, which binds to the G-protein-coupled receptor GPR43 to regulate inflammation and other cancer-related processes. The WNT pathway is central to the maintenance of homeostasis within the large bowel through regulation of processes such as cell proliferation and migration and is frequently aberrantly hyperactivated in colorectal cancers. Abnormal WNT signalling can lead to irregular crypt cell proliferation that favours a hyperproliferative state. Butyrate has been shown to modulate the WNT pathway positively, affecting functional outcomes such as apoptosis and proliferation. Butyrate's ability to regulate gene expression results from epigenetic mechanisms, including its role as a histone deacetylase inhibitor and through modulating DNA methylation and the expression of microRNA. We conclude that genetic and epigenetic modulation of the WNT signalling pathway may be an important mechanism through which butyrate from fermentation of resistant starch and other NDC exert their chemoprotective effects.

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