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Neuroendocrine Interactions in the Control of Glucose- and Energy Homeostasis
Published in André Kleinridders, 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).
Targeting Subgroup-specific Cancer Epitopes for Effective Treatment of Pediatric Medulloblastoma
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Sidharth Mahapatra, Naveenkumar Perumall
The WNT pathway plays a critical role in the proliferation and terminal differentiation of neural progenitor cells [7, 20]. More specifically, signaling through the canonical (WNT-β-catenin) pathway leads to regulation of gene transcription. In healthy cells, the canonical pathway remains inactive due to the absence of WNT, which results in low cytoplasmic concentrations of 0-catenin [7]. A multi-protein complex comprised of axin, adenomatous polyposis coli (APC), casein kinase la (CSK1α), and glycogen synthase kinase 3 (GSK3) binds and phosphorylates β-catenin, thereby promoting polyubiquitination and complete proteolysis [7, 21]. The pathway is activated through the binding of WNT to the Frizzled (FZD) receptor protein on the neuronal cell surface. FZD then phosphorylates Disheveled (DSH), which in turn inactivates the multimeric protein complex responsible for β-catenin degradation [7]. The rising 0-catenin levels shuttle to the nucleus to transcribe proto-oncogenes, such as cyclinD1 (CCND1) and MYC [7, 22].
Dopamine Receptors, Signaling Pathways, and Drugs
Published in Nira Ben-Jonathan, Dopamine, 2020
Frizzled receptors are composed of 10 known genes in the human genome. These receptors range in length from 500 to 700 amino acids. Their extracellular N-terminus contains a cysteine-rich domain, followed by a hydrophilic linker region of 40–100 amino acids. The intracellular C-terminal domain has a variable length and is not well conserved among the different members of the subfamily. Members of this subgroup serve primarily as receptors for the Wnt signaling pathway. Under some classification schemes, the 13 taste receptors are also included within this subgroup.
Discovery and design of G protein-coupled receptor targeting antibodies
Published in Expert Opinion on Drug Discovery, 2023
Sean M. Peterson, Catherine J. Hutchings, Cameron F. Hu, Melina Mathur, Janelle W. Salameh, Fumiko Axelrod, Aaron K. Sato
The human genome contains over 800 GPCRs, of which almost 400 are olfactory receptors. While olfactory receptor expression is mostly limited to the olfactory epithelium, some olfactory receptors are expressed in other tissues and targeting them may have therapeutic benefit [1]. GPCRs are classified according to their sequence homology and phylogenetic analysis of their evolution [2]. The Class A or rhodopsin-like family contains all of the olfactory receptors and many of the clinically targeted receptors including chemokine, amine, and peptide receptors. Class B1 receptors share a large extracellular N-terminus (Figure 1) and Class B2 belong to the adhesion GPCR family. Adhesion GPCRs are particularly intriguing antibody targets because of their unique extended extracellular domains [3]. Class C GPCRs are thought to function as dimers, as are the Class T, taste receptors. Finally, the Class F receptors contain Frizzled and Smoothened, two important GPCRs that regulate organismal development.
Randomized trial of electrodynamic microneedling combined with 5% minoxidil topical solution for treating androgenetic alopecia in Chinese males and molecular mechanistic study of the involvement of the Wnt/β-catenin signaling pathway
Published in Journal of Dermatological Treatment, 2022
Linlin Bao, Haifeng Zong, Sining Fang, Lixiong Zheng, Yuanhong Li
In the present study, the PCR array results suggested that the occurrence of AGA might be related to FZD3 expression. The encoded Frizzled protein FZD3 is a Frizzled transmembrane protein family member and also one of the receptor proteins of the Wnt signaling pathway (28,29). After the ligand Wnt5a binds to the FZD3 protein receptor on the cell membrane surface, it can activate the downstream signaling pathway (30,31). The function of the FZD3 protein is currently unclear and may be associated with follicular development, schizophrenia, and tumor formation (31). Hung et al. (32) showed that FZD3 protein is only expressed in the epidermis and developing hair follicles in mouse skin. The results of PCR and in situ hybridization analysis identified FZD3 protein in the developing epidermis of the 13-day embryonic mice and the hair follicles of 15-day embryonic mice, indicating its function in hair follicle development (32). In 17-day embryonic mice and one-day neonatal mice (the hair follicles only appear in mice three days after birth), FZD3 expression is limited to epithelial keratinocytes (32). In the skin of seven-day-old mice, FZD3 protein is expressed in the entire epidermis and outer cells of hair follicles (32). Thus, FZD3 protein is closely associated with the development of hair follicles. Currently, the literature related to FZD3 expression and hair growth and development presents experimental research in animal models only, and no studies have been carried out in humans.
Targeting Major Signaling Pathways of Bladder Cancer with Phytochemicals: A Review
Published in Nutrition and Cancer, 2021
Connor Chestnut, Dharmalingam Subramaniam, Prasad Dandawate, Subhash Padhye, John Taylor, Scott Weir, Shrikant Anant
The Wnt/β-catenin pathway is highly conserved and critical to both embryological development and carcinogenesis of several cancers (40). Wnt signaling regulates a multitude of cellular processes, including motility, polarity, and stem cell renewal (40). This pathway is initiated by Wnt binding to the membrane receptor Frizzled, which phosphorylates and activates the membrane-bound effector LRP. During the inactive state, β‐catenin is bound by a complex of intracellular proteins called the destruction complex, which mediate β‐catenin ubiquitination and proteasomal degradation (41). Activated LRP induces translocation of the destruction complex to the membrane, where the destruction complex component Disheveled (Dvl) prevents ubiquitination of β‐catenin (41). Rising levels of β‐catenin enter the nucleus and lead to transcription of genes involved in growth and proliferation (41,42).