Neuroendocrine Interactions in the Control of Glucose- and Energy Homeostasis
André Kleinridders in Physiological Consequences of Brain Insulin Action, 2023
The WNT pathway was first described in 1976 when it was reported that Drosophila Melanogaster has a wingless phenotype when this pathway is mutated (92). In 1982, the same signalling cascade was found to promote tumour formation in mice, and therefore given the term ‘integration-1 (int1)’ (93). ‘Wingless’ and ‘int1’ were later combined, and thus, the WNT pathway was coined. The WNT signalling pathway is evolutionarily highly conserved and is classically known for its role in embryogenesis and tumorigenesis (94). Its ligands (WNTs) are involved in three different pathways: the WNT/β-catenin pathway (also known as the canonical WNT pathway), the planar cell polarity pathway, and the WNT/Ca2+ pathway. The canonical WNT pathway is activated when a WNT ligand binds to the frizzled (Fzd) receptor, which subsequently forms a complex with the co-receptor lipoprotein related protein (LRP) 5/6. This causes dishevelled (Dvl) to phosphorylate LRP, which then inactivates GSK3β. Next, GSK3β inactivation decreases phosphorylation of the transcriptional co-activator β-catenin. Stabilized β-catenin then enters the nucleus where it associates with transcription factors of the lymphoid enhancer factor (LEF)/T cell factor (TCF) family, to ultimately regulate the transcription of downstream target genes such as cyclin D1 and axin 2 (95).
Targeted Therapy for Cancer Stem Cells
Surinder K. Batra, Moorthy P. Ponnusamy in Gene Regulation and Therapeutics for Cancer, 2021
Wnt has become a substantial new target for drug development to treat cancer because of its signaling cascade that plays a central role in regulating significant functions of malignant epithelial cells. Wnt ligands and signals drive the Wnt signaling pathway through canonical (β-catenin dependent) or non-canonical (β-catenin independent) paths. The Wnt ligand binds to various transmembrane receptors, such as Frizzled (FZD), Receptor tyrosine kinases (RTKs) and Receptor tyrosine kinase-like orphan receptor (ROR) 1 or ROR2. The pathway is activated with the binding of Wnt ligand to its receptor, followed by the activation of β-catenin. In the absence of Wnt ligand, β-catenin undergoes phosphorylation by a destruction complex containing glycogen synthase kinase 3b (GSK3b), adenomatous polyposis coli (APC) and axin, followed by degradation of β-catenin.
Breast Cancer Stem Cells and Their Niche: Lethal Seeds in Lethal Soil
Brian Leyland-Jones in Pharmacogenetics of Breast Cancer, 2020
The Wnt family of secreted proteins includes the well-characterized canonical Wnt signaling pathway, in which Wnt ligands signal through the stabilization of β-catenin. In this pathway, Wnt proteins bind to a family of frizzled receptors in a complex with the low-density lipoprotein receptor–related proteins 5 and 6 (LRP5/6) coreceptors to activate Dishevelled (Dsh). Subsequently, Dsh inhibits the activity of the β-catenin destruction complex [adenomatous polyposis coli (APC), axin, and glycogen synthase kinase-3β (GSK-3β)], which phosphorylates β-catenin in the absence of the ligands. As a result, β-catenin is stabilized and translocated to the nucleus, where it recruits transactivators to high mobility group (HMG)-box DNA-binding proteins of the lymphoid-enhancer factor/T-cell factor (LEF/TCF) family. In the absence of Wnt signaling, β-catenin remains in the cytoplasm, where it forms the β-catenin destruction complex. GSK-3β phosphorylates β-catenin, which targets the protein for ubiquitin-mediated degradation. When the Wnt pathway is activated, GSK-3β is inhibited, blocking β-catenin phosphorylation and its subsequent degradation (71). In addition, several β-catenin-independent Wnt signaling pathways, known as noncanonical, have been shown to be crucial for different aspects of vertebrate embryo development (71).
Advances of Wnt signalling pathway in dental development and potential clinical application
Published in Organogenesis, 2019
Xi Lu, Jun Yang, Shouliang Zhao, Shangfeng Liu
Recently, advances in the understanding of the Wnt signalling pathway have been made. For example, our previous study suggested a novel inhibitory mechanism of non-canonical Wnt signalling pathway by the direct interaction between Lrp5/6 and Frz, through which the LRP5/6–Frz complex come into being with the function of maintains both canonical and non-canonical pathways in an inactive status at the basal level.9 Twa1 was identified as a new member of canonical Wnt signalling pathway, enhancing the Wnt pathway by accumulating nuclear β-catenin.10 The tumor specific protein C9orf140 compromised Wnt3a induced β-catenin accumulation to negative regulate the Wnt signalling pathway.11 All the novel advances founded in other tissues or species should be highlighted in tooth development.
A Review of Primary Thyroid Lymphoma: Molecular Factors, Diagnosis and Management
Published in Journal of Investigative Surgery, 2019
Efstathios T. Pavlidis, Theodoros E. Pavlidis
Recently, immunohistochemistry has revealed various proteins that are involved in oncogene expression in many malignant tumors. These proteins have been proposed as potential diagnostic biomarkers for early disease detection as well as therapeutic targets. The Wnt signaling pathway consists of these protein families. They are involved in embryonic development as well as carcinogenesis at the molecular level; they define the growth, local invasiveness, lymphatic spread and metastatic capacity of tumor cells.14 A variety of factors derived from the cell (involved in the cytoplasm or nuclei) and extra-cellular space regulate the switch for this signaling pathway. Specific binding receptors and a negative auto-feedback mechanism modulate the production of the induced signals. These glycoproteins are necessary for maintaining tissue integrity in adults, while any abnormality of the Wnt signaling pathway results in the development of disease, either degeneration or cancer.15
The Wnt/β-catenin pathway in breast cancer therapy: a pre-clinical perspective of its targeting for clinical translation
Published in Expert Review of Anticancer Therapy, 2022
Dezaree Raut, Amisha Vora, Lokesh Kumar Bhatt
The Wnt signaling pathway has been known for decades, and there is a clear understanding of its steps and various components. It plays a crucial role in the development of the mammary gland during embryogenesis and pregnancy. But this pathway is dysregulated in breast cancer and has a role in tumorigenesis in breast CSCs. Various endogenous agents directly or indirectly act on this pathway that causes proliferation, invasion, migration, and metastasis of breast cancer. Since discovering the Wnt signaling pathway, many compounds from natural, microbial, and synthetic sources have been identified that can specifically target this pathway in various cancers, including breast cancer. Still, none of these agents are yet available in the market to effectively target this pathway. In addition, few agents are undergoing clinical trials; however, precise modulation of this pathway is necessary and is a challenge for future ongoing trials.
Related Knowledge Centers
- Autocrine Signaling
- Cell Signaling
- Conserved Sequence
- Ligand
- Paracrine Signaling
- Protein
- Signal Transduction
- Cell Surface Receptor
- Frizzled
- Dishevelled