Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities

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Abstract

The Wnt/β-catenin pathway comprises a family of proteins that play critical roles in embryonic development and adult tissue homeostasis. The deregulation of Wnt/β-catenin signalling often leads to various serious diseases, including cancer and non-cancer diseases. Although many articles have reviewed Wnt/β-catenin from various aspects, a systematic review encompassing the origin, composition, function, and clinical trials of the Wnt/β-catenin signalling pathway in tumour and diseases is lacking. In this article, we comprehensively review the Wnt/β-catenin pathway from the above five aspects in combination with the latest research. Finally, we propose challenges and opportunities for the development of small-molecular compounds targeting the Wnt signalling pathway in disease treatment.

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Most cited references 357

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Wnt/β-Catenin Signaling, Disease, and Emerging Therapeutic Modalities.

Roel Nusse, Hans Clevers (2017)

The WNT signal transduction cascade is a main regulator of development throughout the animal kingdom. Wnts are also key drivers of most types of tissue stem cells in adult mammals. Unsurprisingly, mutated Wnt pathway components are causative to multiple growth-related pathologies and to cancer. Here, we describe the core Wnt/β-catenin signaling pathway, how it controls stem cells, and contributes to disease. Finally, we discuss strategies for Wnt-based therapies.

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Identification of stem cells in small intestine and colon by marker gene Lgr5.

Nick Barker, Johan H van Es, Jeroen Kuipers … (2007)

The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. It is currently believed that four to six crypt stem cells reside at the +4 position immediately above the Paneth cells in the small intestine; colon stem cells remain undefined. Lgr5 (leucine-rich-repeat-containing G-protein-coupled receptor 5, also known as Gpr49) was selected from a panel of intestinal Wnt target genes for its restricted crypt expression. Here, using two knock-in alleles, we reveal exclusive expression of Lgr5 in cycling columnar cells at the crypt base. In addition, Lgr5 was expressed in rare cells in several other tissues. Using an inducible Cre knock-in allele and the Rosa26-lacZ reporter strain, lineage-tracing experiments were performed in adult mice. The Lgr5-positive crypt base columnar cell generated all epithelial lineages over a 60-day period, suggesting that it represents the stem cell of the small intestine and colon. The expression pattern of Lgr5 suggests that it marks stem cells in multiple adult tissues and cancers.

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Wnt/beta-catenin signaling: components, mechanisms, and diseases.

Bryan T MacDonald, Keiko Tamai, Xi. He (2009)

Signaling by the Wnt family of secreted glycolipoproteins via the transcriptional coactivator beta-catenin controls embryonic development and adult homeostasis. Here we review recent progress in this so-called canonical Wnt signaling pathway. We discuss Wnt ligands, agonists, and antagonists, and their interactions with Wnt receptors. We also dissect critical events that regulate beta-catenin stability, from Wnt receptors to the cytoplasmic beta-catenin destruction complex, and nuclear machinery that mediates beta-catenin-dependent transcription. Finally, we highlight some key aspects of Wnt/beta-catenin signaling in human diseases including congenital malformations, cancer, and osteoporosis, and discuss potential therapeutic implications.

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Author and article information

Contributors

Gang Yin:

ORCID: http://orcid.org/0000-0003-3753-0753

gangyin@csu.edu.cn

Journal

Journal ID (nlm-ta): Signal Transduct Target Ther

Journal ID (iso-abbrev): Signal Transduct Target Ther

Title: Signal Transduction and Targeted Therapy

Publisher: Nature Publishing Group UK (London )

ISSN (Print): 2095-9907

ISSN (Electronic): 2059-3635

Publication date (Electronic): 3 January 2022

Publication date PMC-release: 3 January 2022

Publication date Collection: 2022

Volume: 7

Electronic Location Identifier: 3

Affiliations

[1 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, Department of Pathology, Xiangya Hospital, , School of Basic Medical Sciences, Central South University, ; Changsha, 410013 China

[2 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, Department of Histology and Embryology, , School of Basic Medical Sciences, Central South University, ; Changsha, 410013 China

[3 ]GRID grid.216417.7, ISNI 0000 0001 0379 7164, China-Africa Research Center of Infectious Diseases, , School of Basic Medical sciences, Central South University, ; Changsha, 410013 China

Author information

Gang Yin http://orcid.org/0000-0003-3753-0753

Article

Publisher ID: 762

DOI: 10.1038/s41392-021-00762-6

PMC ID: 8724284

PubMed ID: 34980884

SO-VID: a3ff8351-305c-46cb-aa68-f024747a700f

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 22 February 2021

Date revision received : 28 June 2021

Date accepted : 7 July 2021

Funding

Funded by: the National Key R&D Program of China, Stem Cell and Translational Research,No.2016YFA0102000

Funded by: Student Innovation Project of Central South University,No.1053320183731

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Keywords: oncogenes,drug regulation,cancer genetics,non-coding rnas,self-renewal

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Keywords: oncogenes, drug regulation, cancer genetics, non-coding rnas, self-renewal

Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities

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Stress signalling in stem cells

Most cited references 357

Wnt/β-Catenin Signaling, Disease, and Emerging Therapeutic Modalities.

Identification of stem cells in small intestine and colon by marker gene Lgr5.

Wnt/beta-catenin signaling: components, mechanisms, and diseases.

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