The Wnt Pathway: From Signaling Mechanisms to Synthetic Modulators

Annual Review of Biochemistry, Год журнала: 2022, Номер 91(1), С. 571 - 598

Опубликована: Март 19, 2022

The Wnt pathway is central to a host of developmental and disease-related processes. remarkable conservation this intercellular signaling cascade throughout metazoan lineages indicates that it coevolved with multicellularity regulate the generation spatial arrangement distinct cell types. By regulating fate specification, mitotic activity, polarity, orchestrates development tissue homeostasis, its dysregulation implicated in defects, cancer, degenerative disorders. We review advances our understanding key pathway, from protein production secretion relay signal cytoplasm receiving cell. discuss evolutionary history as well endogenous synthetic modulators activity. Finally, we highlight remaining gaps knowledge transduction avenues for future research.

Язык: Английский

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Wnt some lose some: transcriptional governance of stem cells by Wnt/β-catenin signaling

Genes & Development, Год журнала: 2014, Номер 28(14), С. 1517 - 1532

Опубликована: Июль 15, 2014

In mammals, Wnt/β-catenin signaling features prominently in stem cells and cancers, but how for what purposes have been matters of much debate. this review, we summarize our current knowledge its downstream transcriptional regulators normal malignant cells. We centered review largely on three types cells—embryonic cells, hair follicle intestinal epithelial cells—in which the roles extensively studied. Using these models, unravel many controversial issues surrounding Wnt resolved by dissecting diversity circuitry effectors, often leading to opposite outcomes Wnt/β-catenin-mediated regulation differences rooted stage- context-dependent effects .

Язык: Английский

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In vivo base editing of post-mitotic sensory cells

Nature Communications, Год журнала: 2018, Номер 9(1)

Опубликована: Май 30, 2018

Abstract Programmable nucleases can introduce precise changes to genomic DNA through homology-directed repair (HDR). Unfortunately, HDR is largely restricted mitotic cells, and typically accompanied by an excess of stochastic insertions deletions (indels). Here we present in vivo base editing strategy that addresses these limitations. We use nuclease-free install a S33F mutation β-catenin blocks phosphorylation, impedes degradation, upregulates Wnt signaling. In vitro, installs the with 200-fold higher editing:indel ratio than HDR. post-mitotic cells mouse inner ear, injection editor protein:RNA:lipid this mutation, resulting activation induces mitosis cochlear supporting cellular reprogramming. contrast, agents does not induce upregulation. These results establish for modifying posttranslational states signaling pathways, approach precision tissues.

Язык: Английский

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WNT Signaling in Melanoma

International Journal of Molecular Sciences, Год журнала: 2020, Номер 21(14), С. 4852 - 4852

Опубликована: Июль 9, 2020

WNT-signaling controls important cellular processes throughout embryonic development and adult life, so any deregulation of this signaling can result in a wide range pathologies, including cancer. is classified into two categories: β-catenin-dependent (canonical pathway) β-catenin-independent (non-canonical pathway), the latter be further divided WNT/planar cell polarity (PCP) calcium pathways. WNT ligands are considered as unique directional growth factors that contribute to both proliferation polarity. Origin cancer diverse therefore tissue-specific differences found between cancers, specific mutations contributing development. This review focuses on role pathway melanoma. The current view immunity well short summary pathway-related drugs under investigation also provided.

Язык: Английский

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Multi‑layered prevention and treatment of chronic inflammation, organ fibrosis and cancer associated with canonical WNT/β‑catenin signaling activation (Review)

International Journal of Molecular Medicine, Год журнала: 2018, Номер unknown

Опубликована: Май 17, 2018

β‑catenin/CTNNB1 is an intracellular scaffold protein that interacts with adhesion molecules (E‑cadherin/CDH1, N‑cadherin/CDH2, VE‑cadherin/CDH5 and α‑catenins), transmembrane‑type mucins (MUC1/CD227 MUC16/CA125), signaling regulators (APC, AXIN1, AXIN2 NHERF1/EBP50) epigenetic or transcriptional (BCL9, BCL9L, CREBBP/CBP, EP300/p300, FOXM1, MED12, SMARCA4/BRG1 TCF/LEF). Gain‑of‑function CTTNB1 mutations are detected in bladder cancer, colorectal gastric liver lung pancreatic prostate cancer uterine whereas loss‑of‑function CTNNB1 also human cancer. ABCB1, ALDH1A1, ASCL2, ATF3, AXIN2, BAMBI, CCND1, CD44, CLDN1, CTLA4, DKK1, EDN1, EOMES, FGF18, FGF20, FZD7, IL10, JAG1, LEF1, LGR5, MITF, MSX1, MYC, NEUROD1, NKD1, NODAL, NOTCH2, NOTUM, NRCAM, OPN, PAX3, PPARD, PTGS2, RNF43, SNAI1, SP5, TCF7, TERT, TNFRSF19, VEGFA ZNRF3 representative β‑catenin target genes. involved myofibroblast activation subsequent pulmonary fibrosis, addition to other types of fibrosis. NF‑κB field cancerization the stomach associated Helicobacter pylori (H. pylori) infection hepatitis C virus (HCV) etiologies. β‑catenin‑targeted therapeutics functionally classified into inhibitors targeting upstream (AZ1366, ETC‑159, G007‑LK, GNF6231, ipafricept, NVP‑TNKS656, rosmantuzumab, vantictumab, WNT‑C59, WNT974 XAV939), protein‑protein interactions (CGP049090, CWP232228, E7386, ICG‑001, LF3 PRI‑724), (PKF118‑310), mediator complexes (CCT251545 cortistatin A) outputs, including CD44v6, FZD7 LGR5. Eradicating H. HCV optimal approach for first‑line prevention hepatocellular carcinoma (HCC), respectively. However, may be applicable organ second‑line HCC treating β‑catenin‑driven The multi‑layered treatment strategy β‑catenin‑related diseases necessary practice personalized medicine implementation precision medicine.

Язык: Английский

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Stem cell proliferation is induced by apoptotic bodies from dying cells during epithelial tissue maintenance

Nature Communications, Год журнала: 2019, Номер 10(1)

Опубликована: Март 5, 2019

Abstract Epithelial tissues require the removal and replacement of damaged cells to sustain a functional barrier. Dying provide instructive cues that can influence surrounding proliferate, but how these signals are transmitted their healthy neighbors control cellular behaviors during tissue homeostasis remains poorly understood. Here we show dying stem facilitate communication with adjacent by caspase-dependent production Wnt8a-containing apoptotic bodies drive turnover in living epithelia. Basal engulf bodies, activate Wnt signaling, stimulated divide maintain tissue-wide cell numbers. Inhibition either death or signaling eliminated apoptosis-induced division, while overexpression Wnt8a combined induced led an expansion population. We conclude ingestion represents regulatory mechanism linking division overall numbers epithelial homeostasis.

Язык: Английский

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Modulation of the Wnt pathway through inhibition of CLK2 and DYRK1A by lorecivivint as a novel, potentially disease-modifying approach for knee osteoarthritis treatment

Osteoarthritis and Cartilage, Год журнала: 2019, Номер 27(9), С. 1347 - 1360

Опубликована: Май 25, 2019

ObjectivesWnt pathway upregulation contributes to knee osteoarthritis (OA) through osteoblast differentiation, increased catabolic enzymes, and inflammation. The small-molecule Wnt inhibitor, lorecivivint (SM04690), which previously demonstrated chondrogenesis cartilage protection in an animal OA model, was evaluated elucidate its mechanism of action.DesignBiochemical assays measured kinase activity. Western blots protein phosphorylation human mesenchymal stem cells (hMSCs), chondrocytes, synovial fibroblasts. siRNA knockdown effects hMSCs BEAS-2B on pathway, chondrogenic genes, LPS-induced inflammatory cytokines by qPCR. In vivo anti-inflammation, pain, function were following single intra-articular (IA) or vehicle injection the monosodium iodoacetate (MIA)-induced rat model.ResultsLorecivivint inhibited intranuclear kinases CDC-like 2 (CLK2) dual-specificity tyrosine phosphorylation-regulated 1A (DYRK1A). Lorecivivint CLK2-mediated serine/arginine-rich (SR) splicing factors DYRK1A-mediated SIRT1 FOXO1. knockdowns identified a role for CLK2 DYRK1A modulation without affecting β-catenin with inhibition inducing early enhancing mature chondrocyte function. NF-κB STAT3 reduced sufficient anti-inflammatory effects, while combined DYRK1A/CLK2 enhanced this effect. MIA production degradative resulting joint cartilage, decreased improved weight-bearing function.ConclusionsLorecivivint suggested novel inhibition, chondrogenesis, function, anti-inflammation. shows potential modify structure improve symptoms OA.

Язык: Английский

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Targeting Cancer Stem Cells in Triple-Negative Breast Cancer

Cancers, Год журнала: 2019, Номер 11(7), С. 965 - 965

Опубликована: Июль 9, 2019

Triple-negative breast cancer (TNBC) is a highly aggressive form of that lacks targeted therapy options, and patients diagnosed with TNBC have poorer outcomes than other subtypes. Emerging evidence suggests stem cells (BCSCs), which tumor-initiating potential possess self-renewal capacity, may be responsible for this poor outcome by promoting resistance, metastasis, recurrence. been consistently reported to display cell (CSC) signatures at functional, molecular, transcriptional levels. In recent decades, CSC-targeting strategies shown therapeutic effects on in multiple preclinical studies, some these are currently being evaluated clinical trials. Therefore, understanding CSC biology has the guide discovery novel agents future. review, we focus signaling pathways (SRSPs) aberrantly activated discuss specific components involved cells. Additionally, describe molecular mechanisms shared both CSCs, including metabolic plasticity, enables switch between according substrate availability meet energetic biosynthetic demands rapid growth survival under harsh conditions. We highlight CSCs as key regulators driving aggressiveness TNBC. Thus, manipulation can strategy

Язык: Английский

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Akkermansia muciniphila in neuropsychiatric disorders: friend or foe?

Frontiers in Cellular and Infection Microbiology, Год журнала: 2023, Номер 13

Опубликована: Июль 10, 2023

An accumulating body of evidence suggests that the bacterium Akkermansia muciniphila exhibits positive systemic effects on host health, mainly by improving immunological and metabolic functions, it is therefore regarded as a promising potential probiotic. Recent clinical preclinical studies have shown A. plays vital role in variety neuropsychiatric disorders influencing brain through microbiota-gut-brain axis (MGBA). Numerous observed its substances can effectively improve symptoms restoring gut microbiota, reestablishing integrity mucosal barrier, regulating immunity, modulating neuroinflammation. However, was also reported to participate development aggravating inflammation mucus production. Therefore, exact mechanism action remains much controversial. This review summarizes proposed roles mechanisms various neurological psychiatric such depression, anxiety, Parkinson’s disease, Alzheimer’s multiple sclerosis, strokes, autism spectrum disorders, provides insights into therapeutic application for treatment these conditions.

Язык: Английский

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Microbial signatures and therapeutic strategies in neurodegenerative diseases

Biomedicine & Pharmacotherapy, Год журнала: 2025, Номер 184, С. 117905 - 117905

Опубликована: Фев. 10, 2025

Язык: Английский

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