Activating Wnt/β-catenin signaling pathway for disease therapy: Challenges and opportunities

Huang, Piao; Yan, Rong; Zhao, Xue; Wang, Lei; Ke, Xisong; Qu, Yi

doi:10.1016/j.pharmthera.2018.11.008

Cited by 197 publications

(125 citation statements)

References 134 publications

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“…Owing to its crucial function in stem cell maintenance and tissue homeostasis, there are potential risks and concerns for modulation of WβC‐signalling, regarding both the safety and selectivity, underscoring “Dr. Jekyll'‐Mr Hyde's” dual facet of WβC‐signalling activation/inhibition (Banerjee et al, ; Chen et al, ; Herrera‐Arozamena, Martí‐Marí, Estrada, Fuente Revenga, & Rodríguez‐Franco, ; Huang, Tang, et al, ; Huang, Yan, et al, ; Janda et al, ; Kahn, ; Mahmood, Bhatti, Syed, & John, ; Maiese, ; Narcisi et al, ; Nusse & Clevers, ). Therefore, indirect WβC modulation appears as an attractive strategy to up‐regulate endogenous neurogenesis.…”

Section: Therapeutic Modulation Of Wnt/β‐catenin Signallingmentioning

confidence: 99%

“…The authors also identified the critical residues on Axin for HLY78 binding and showed that HLY78 may weaken the autoinhibition of Axin (Wang et al, ). Further results have been recently gathered by Chen et al () on the design, synthesis and structure‐activity relationship for optimization of phenanthridine derivatives as new WβC‐signalling pathway agonists, including evidence for a protective role of the Wnt‐agonists in in vivo cytotoxicity models (Huang, Tang, et al, ; Huang, Yan, et al, ). Recently, protein phosphatase‐2A (PP2A), a multi‐subunit serine/threonine phosphatase that positively regulates the Wnt pathway, has been shown to directly interact with Axin, APC, and β‐catenin, and thus identified as a target of the Wnt agonist/IQ and sodium selenate (Jin et al, ).…”

Section: Therapeutic Modulation Of Wnt/β‐catenin Signallingmentioning

confidence: 99%

“…Owing to its crucial function in stem cell maintenance and tissue ho- Huang , Tang, et al, 2019a;Huang, Yan, et al, 2019b;Janda et al, 2017;Kahn, 2014;Mahmood, Bhatti, Syed, & John, 2016;Maiese, 2015;Narcisi et al, 2016;Nusse & Clevers, 2017). Therefore, indirect WβC interesting therapeutic potentials for NDs including PD (Table 1 and 2 and Figure 7).…”

Section: Up-regulating Adult Neurogenenesis As a Disease Modifying mentioning

confidence: 99%

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Parkinson's disease, aging and adult neurogenesis: Wnt/β‐catenin signalling as the key to unlock the mystery of endogenous brain repair

et al. 2020

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A common hallmark of age‐dependent neurodegenerative diseases is an impairment of adult neurogenesis. Wingless‐type mouse mammary tumor virus integration site (Wnt)/β‐catenin (WβC) signalling is a vital pathway for dopaminergic (DAergic) neurogenesis and an essential signalling system during embryonic development and aging, the most critical risk factor for Parkinson's disease (PD). To date, there is no known cause or cure for PD. Here we focus on the potential to reawaken the impaired neurogenic niches to rejuvenate and repair the aged PD brain. Specifically, we highlight WβC‐signalling in the plasticity of the subventricular zone (SVZ), the largest germinal region in the mature brain innervated by nigrostriatal DAergic terminals, and the mesencephalic aqueduct‐periventricular region (Aq‐PVR) Wnt‐sensitive niche, which is in proximity to the SNpc and harbors neural stem progenitor cells (NSCs) with DAergic potential. The hallmark of the WβC pathway is the cytosolic accumulation of β‐catenin, which enters the nucleus and associates with T cell factor/lymphoid enhancer binding factor (TCF/LEF) transcription factors, leading to the transcription of Wnt target genes. Here, we underscore the dynamic interplay between DAergic innervation and astroglial‐derived factors regulating WβC‐dependent transcription of key genes orchestrating NSC proliferation, survival, migration and differentiation. Aging, inflammation and oxidative stress synergize with neurotoxin exposure in “turning off” the WβC neurogenic switch via down‐regulation of the nuclear factor erythroid‐2‐related factor 2/Wnt‐regulated signalosome, a key player in the maintenance of antioxidant self‐defense mechanisms and NSC homeostasis. Harnessing WβC‐signalling in the aged PD brain can thus restore neurogenesis, rejuvenate the microenvironment, and promote neurorescue and regeneration.

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Section: Therapeutic Modulation Of Wnt/β‐catenin Signallingmentioning

confidence: 99%

Section: Therapeutic Modulation Of Wnt/β‐catenin Signallingmentioning

confidence: 99%

Section: Up-regulating Adult Neurogenenesis As a Disease Modifying mentioning

confidence: 99%

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Parkinson's disease, aging and adult neurogenesis: Wnt/β‐catenin signalling as the key to unlock the mystery of endogenous brain repair

et al. 2020

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“…Specifically, in the activated Wnt/β-catenin pathway, the degradation complex of β-catenin, AXIN/APC/ GSK3β/CK1 complex is depolymerized [17]. β-catenin aggregates within the plasma and enters the nucleus to combine with TCF/LEF, which in turn activates the transcription of down-stream genes.…”

Section: Discussionmentioning

confidence: 99%

“…Wnt/β-catenin signaling pathway is not only an important way to regulate the early development of embryonic, maintain tissue homeostasis in adults and central nervous system regeneration, but also closely related to cell proliferation, differentiation, migration and apoptosis [12][13][14]. The abnormal regulation of Wnt/β-catenin signal is closely related to many diseases [15][16][17]. In the absence of Wnt ligands, the Wnt/β-catenin signaling pathway is in a " off " state, and β-catenin is at a low level under the control of ubiquitin proteasome system [18].…”

mentioning

confidence: 99%

Beta-catenin inhibits bovine parainfluenza virus type 3 replication via innate immunity pathway

et al. 2020

BMC Vet Res

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Background: Bovine parainfluenza virus type 3 (BPIV3) is one of the important viral respiratory agents associated with the bovine respiratory disease complex (BRDC) in cattle. Previous study has demonstrated that infection of BPIV3 causes innate immune response within the host cell. β-catenin is a key component of the Wnt/β-catenin signal pathway which is involved in the regulation of interferon-beta (IFN-β) transcription. Some viruses can activate while others can inhibit the Wnt/β-catenin signaling pathway. However, the role of β-catenin in BPIV3 infection remains unclear.Results: Here we found that the expression of β-catenin mRNA was up-regulated and β-catenin protein was downregulated after BPIV3 infection in MDBK cells. Moreover, it was confirmed that overexpression of β-catenin suppressed BPIV3 replication and knockdown of β-catenin promoted viral replication, suggesting that β-catenin inhibits BPIV3 replication. Furthermore, IFN-β signal pathway and virus titer analysis using the GSK3β inhibitor (LiCl) revealed that Wnt/β-catenin can serve as a mechanism to suppress virus replication in infected cells. The results indicated that LiCl promoted the expression and accumulation in the nucleus of β-catenin, which further promoted the expression of IFN-β and OSA1 and suppressed BPIV3 replication. Most importantly, BPIV3 down-regulating βcatenin protein expression was due to degradation of GSK3β mediated proteasome pathway. Conclusions: In summary, we discovered the relationship between β-catenin and BPIV3 replication. These results provided further insight into the study of BPIV3 pathogenesis.

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ASPM promotes hepatocellular carcinoma progression by activating Wnt/β‐catenin signaling through antagonizing autophagy‐mediated Dvl2 degradation

et al. 2021

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Hepatocellular carcinoma (HCC) is one of the most fatal cancers worldwide. Here, we show that expression of abnormal spindle-like microcephaly-associated (ASPM) is upregulated in liver cancer samples and this upregulation is significantly associated with tumor aggressiveness and reduced survival times of patients. Downregulation of ASPM expression inhibits the proliferation, invasion, migration and epithelial-to-mesenchymal transition of HCC cells in vitro, and inhibits tumor formation in nude mice. ASPM interacts with disheveled-2 (Dvl2) and antagonizes autophagy-mediated Dvl2 degradation by weakening the functional interaction between Dvl2 and the lipidated form of microtubule-associated proteins 1A/1B light chain 3A (LC3II), thereby increasing Dvl2 protein abundance and leading to Wnt/β-catenin signaling activation in HCC cells. Thus, our results define ASPM as a novel oncoprotein in HCC and indicate that disruption of the Wnt-ASPM-Dvl2-β-catenin signaling axis might have potential clinical value.

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Activating Wnt/β-catenin signaling pathway for disease therapy: Challenges and opportunities

Cited by 197 publications

References 134 publications

Parkinson's disease, aging and adult neurogenesis: Wnt/β‐catenin signalling as the key to unlock the mystery of endogenous brain repair

Parkinson's disease, aging and adult neurogenesis: Wnt/β‐catenin signalling as the key to unlock the mystery of endogenous brain repair

Beta-catenin inhibits bovine parainfluenza virus type 3 replication via innate immunity pathway

ASPM promotes hepatocellular carcinoma progression by activating Wnt/β‐catenin signaling through antagonizing autophagy‐mediated Dvl2 degradation

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