Wnt signaling pathway: A comprehensive review

Hayat, Rabia; Manzoor, Maleeha; Hussain, Ali

doi:10.1002/cbin.11797

Cited by 119 publications

(86 citation statements)

References 140 publications

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“…Wnt is another major pathway blocked by Klotho (Liu H, et al, 2007). Wnt is a signaling cascade involved in embryogenesis, stem cell biology, cell fate specification, polarity, mitosis and migration, as recently reviewed ( Hayat et al, 2022 ; Rim et al, 2022 ). Wnt dysregulation results in anomalies of development, various degenerative conditions and cancer.…”

Section: Klotho Functions Independent Of Fgf23mentioning

confidence: 99%

“…Wnt dysregulation results in anomalies of development, various degenerative conditions and cancer. There is a canonical β-catenin dependent pathway, and a non-canonical (β-catenin independent) pathway ( Hayat et al, 2022 ). Non-canonical has two subtypes, i.e., the planar cell polarity and the Wnt/Ca 2+ pathways.…”

Section: Klotho Functions Independent Of Fgf23mentioning

confidence: 99%

“…However, following the binding of a Wnt ligand to Frizzle and coreceptor LRP, the degradation of β-catenin is terminated, and it can migrate into the nucleus to activate target genes through interactions with the T-cell factor/lymphoid enhancer-binding factor (TCF/LEF) transcription factors. This canonical pathway regulates mainly cell proliferation, involving cyclin D1, c-myc and many other proteins; whereas the non-canonical pathways regulate cell polarity and motility ( Hayat et al, 2022 ). The proliferative aspects are particularly relevant to cancer, such as colon cancer and hepatocellular carcinoma.…”

Section: Klotho Functions Independent Of Fgf23mentioning

confidence: 99%

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Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations

Prud’homme

Kurt²,

Wang

2022

Front. Aging

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The α-Klotho protein (henceforth denoted Klotho) has antiaging properties, as first observed in mice homozygous for a hypomorphic Klotho gene (kl/kl). These mice have a shortened lifespan, stunted growth, renal disease, hyperphosphatemia, hypercalcemia, vascular calcification, cardiac hypertrophy, hypertension, pulmonary disease, cognitive impairment, multi-organ atrophy and fibrosis. Overexpression of Klotho has opposite effects, extending lifespan. In humans, Klotho levels decline with age, chronic kidney disease, diabetes, Alzheimer’s disease and other conditions. Low Klotho levels correlate with an increase in the death rate from all causes. Klotho acts either as an obligate coreceptor for fibroblast growth factor 23 (FGF23), or as a soluble pleiotropic endocrine hormone (s-Klotho). It is mainly produced in the kidneys, but also in the brain, pancreas and other tissues. On renal tubular-cell membranes, it associates with FGF receptors to bind FGF23. Produced in bones, FGF23 regulates renal excretion of phosphate (phosphaturic effect) and vitamin D metabolism. Lack of Klotho or FGF23 results in hyperphosphatemia and hypervitaminosis D. With age, human renal function often deteriorates, lowering Klotho levels. This appears to promote age-related pathology. Remarkably, Klotho inhibits four pathways that have been linked to aging in various ways: Transforming growth factor β (TGF-β), insulin-like growth factor 1 (IGF-1), Wnt and NF-κB. These can induce cellular senescence, apoptosis, inflammation, immune dysfunction, fibrosis and neoplasia. Furthermore, Klotho increases cell-protective antioxidant enzymes through Nrf2 and FoxO. In accord, preclinical Klotho therapy ameliorated renal, cardiovascular, diabetes-related and neurodegenerative diseases, as well as cancer. s-Klotho protein injection was effective, but requires further investigation. Several drugs enhance circulating Klotho levels, and some cross the blood-brain barrier to potentially act in the brain. In clinical trials, increased Klotho was noted with renin-angiotensin system inhibitors (losartan, valsartan), a statin (fluvastatin), mTOR inhibitors (rapamycin, everolimus), vitamin D and pentoxifylline. In preclinical work, antidiabetic drugs (metformin, GLP-1-based, GABA, PPAR-γ agonists) also enhanced Klotho. Several traditional medicines and/or nutraceuticals increased Klotho in rodents, including astaxanthin, curcumin, ginseng, ligustilide and resveratrol. Notably, exercise and sport activity increased Klotho. This review addresses molecular, physiological and therapeutic aspects of Klotho.

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Section: Klotho Functions Independent Of Fgf23mentioning

confidence: 99%

Section: Klotho Functions Independent Of Fgf23mentioning

confidence: 99%

Section: Klotho Functions Independent Of Fgf23mentioning

confidence: 99%

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Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations

Prud’homme

Kurt²,

Wang

2022

Front. Aging

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“…The Wnt/β-catenin signaling pathway is an evolutionary cell-to-cell coordination mechanism that is essential for a wide range of physiological processes, such as stem cell regeneration, proliferation, and migration. Hypo or hyper-activation of various signaling pathways is linked to the progression of various human disorders, most notably cancers ( 16 ). Alterations in the Wnt/β-catenin pathway contribute to the development/progression of several types of cancer, including NSCLC ( 17 ).…”

Section: Introductionmentioning

confidence: 99%

miR‑29a‑3p inhibits the malignant characteristics of non‑small cell lung cancer cells by reducing the activity of the Wnt/β‑catenin signaling pathway

Zhang

Han

et al. 2022

Oncol Lett

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MicroRNAs (miRNAs) can influence non-small cell lung cancer (NSCLC) in a tumor-suppressive and oncogenic manner. The present study aimed to investigate the effects and underlying mechanisms of miR-29a-3p in NSCLC. NSCLC cell lines (A549, H1299, and H460) and a normal lung epithelial cell line (BEAS-2B) were used. Additionally, a mouse lung tumor xenograft model was established using A549 cells and used to determine the effects of miR-29a-3p on NSCLC in vivo. Tumor volumes were measured every week. The expression of miR-29a-3p in cells and lung tissues were detected by RT-qPCR. Cell proliferation was detected using Cell Counting Kit-8 and EdU assays. Migration and invasion were assessed using wound healing and Transwell invasion assays, respectively. Ki-67 expression was detected using immunohistochemical staining. The expression levels of Wnt3a and β-catenin were determined using western blotting. miR-29a-3p expression was significantly downregulated in NSCLC cells and mice. In contrast to miR-29a-3p knockdown, miR-29a-3p overexpression decreased NSCLC cell proliferation, migration, and invasion as well as tumor growth in in the NSCLC mouse model. Moreover, miR-29a-3p overexpression decreased the protein expression levels of Wnt3a and β-catenin. The inhibitory effects of miR-29a-3p on NSCLC cells were reversed by LiCl (an activator of the Wnt signaling pathway). In conclusion, miR-29a-3p prevented NSCLC tumor growth and cell proliferation, migration, and invasion by inhibiting the Wnt/β-catenin signaling pathway. This finding offers novel insights into the prognosis and treatment of NSCLC.

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“…The family of WNT proteins contains 19 cysteine-rich, secreted ligands which bind to Frizzled (FZD) receptors located in the plasma membrane of target cells [25] . WNT proteins comprise between 350 and 400 amino acids and are subject to numerous post-translational modifications including disulfide-bonds, glycosylation and palmitoyleation [12] , [25] , [30] . The characteristic distribution of the 22 cysteines results in the formation of disulfide bonds required for proper folding of the protein [20] , [24] , [30] .…”

Section: Introductionmentioning

confidence: 99%