Axin2-Mesenchymal PDL Cells, Instead of K14 Epithelial Cells, Play a Key Role in Rapid Cementum Growth.
Journal of dental research
To date, attempts to regenerate functional periodontal tissues (including cementum) are largely unsuccessful due to a lack of full understanding about the cellular origin (epithelial or mesenchymal cells) essential for root cementum growth. To address this issue, we first identified a rapid cementum growth window from the ages of postnatal day 28 (P28) to P56. Next, we showed that expression patterns of Axin2 and β-catenin within cementum-forming periodontal ligament (PDL) cells are negatively associated with rapid cementum growth. Furthermore, cell lineage tracing studies revealed that the Axin2-mesenchymal PDL cells and their progeny rapidly expand and directly contribute to postnatal acellular and cellular cementum growth. In contrast, the number of K14 epithelial cells, which were initially active at early stages of development, was reduced during rapid cementum formation from P28 to P56. The in vivo cell ablation of these Axin2 cells using ; mice led to severe cementum hypoplasia, whereas constitutive activation of β-catenin in the Axin2 cells resulted in an acceleration in cellular cementogenesis plus a transition from acellular cementum to cellular cementum. Thus, we conclude that Axin2-mesenchymal PDL cells, instead of K14 epithelial cells, significantly contribute to rapid cementum growth.
10.1177/0022034519871021
Axin2-expressing cells in the periodontal ligament are regulated by bone morphogenetic protein signalling and play a pivotal role in periodontium development.
Journal of clinical periodontology
AIM:To date, controversies still exist regarding the exact cellular origin and regulatory mechanisms of periodontium development, which hinders efforts to achieve ideal periodontal tissue regeneration. Axin2-expressing cells in the periodontal ligament (PDL) have been shown to be a novel progenitor cell population that is essential for periodontal homeostasis. In the current study, we aimed to elucidate the regulatory role of bone morphogenetic protein receptor type 1A (BMPR1A)-mediated BMP signalling in Axin2-expressing cells during periodontium development. MATERIALS AND METHODS:Two strains of Axin2 gene reporter mice, Axin2 and Axin2 ; R26R mice, were used. We next generated Axin2 ; R26R ; R26R mice to genetically ablate of Axin2-lineage cells. Axin2 ; Bmpr1a ; R26R mice were established to conditionally knock out Bmpr1a in Axin2-lineage cells. Multiple approaches, including micro-computed tomography, calcein green, and alizarin red double-labelling, scanning electron microscopy, and histological and immunostaining assays, were used to analyse periodontal phenotypes and molecular mechanisms. RESULTS:X-gal staining revealed that Axin2-expressing cells in the PDL were mainly distributed along the alveolar bone and cementum surface. Cell lineage tracing and cell ablation assays further demonstrated the indispensable role of Axin2-expressing cells in periodontium development. Next, we found that conditional knockout of Bmpr1a in Axin2-lineage cells led to periodontal defects, which were characterized by alveolar bone loss, impaired cementogenesis, and abnormal Sharpey's fibres. CONCLUSIONS:Our findings suggest that Axin2-expressing cells in the PDL are essential for periodontium development, which is regulated by BMP signalling.
10.1111/jcpe.13666
AXIN1 and AXIN2 variants in gastrointestinal cancers.
Mazzoni Serina M,Fearon Eric R
Cancer letters
Mutations in the APC (adenomatous polyposis coli) gene, which encodes a multi-functional protein with a well-defined role in the canonical Wnt pathway, underlie familial adenomatous polypsosis, a rare, inherited form of colorectal cancer (CRC) and contribute to the majority of sporadic CRCs. However, not all sporadic and familial CRCs can be explained by mutations in APC or other genes with well-established roles in CRC. The AXIN1 and AXIN2 proteins function in the canonical Wnt pathway, and AXIN1/2 alterations have been proposed as key defects in some cancers. Here, we review AXIN1 and AXIN2 sequence alterations reported in gastrointestinal cancers, with the goal of vetting the evidence that some of the variants may have key functional roles in cancer development.
10.1016/j.canlet.2014.09.018
Axin PPI Networks: New Interacting Proteins and New Targets?
Song Xiaomin,Cai Wenwen,Li Lin
Current topics in medicinal chemistry
The scaffold protein Axin plays important roles in multiple signaling pathways through mediating the formation of different signaling complexes. Axin is best known for its role as a negative regulator in Wnt/β-catenin pathway. Aberrant activation of the key components in Wnt/β-catenin pathway including Axin has been linked to a variety of human cancers. Drugs developed for this pathway are far from satisfying largely due to the limited targets especially enzymesin this pathway. Almost all Axinsignal pathways depend on a number of protein-protein interactions (PPIs) for transmitting information, making PPIs attractive targets and probably a future direction for drug discovery. Axin interacts with a plethora of proteins, positively or negatively regulating several signaling pathways that are closely involved in the pathogenesis of human disease. Studies in recent years indicated Axin as a promising target for treating Wnt-driven diseases. With the identification of more interacting partners for Axin and increased understanding about the roles of these Axin-mediated PPIs in human disease, new targets may surface from the Axin PPI networks, which may lead to the generation of new drugs and treatmentstrategies. In this review, we outline the Axin PPI networks in several pathways especially in Wnt signaling and discuss how those Axin-interacting proteins affect the respective signaling pathways through an interaction with Axin.
The Scaffold Protein Axin Promotes Signaling Specificity within the Wnt Pathway by Suppressing Competing Kinase Reactions.
Gavagan Maire,Fagnan Erin,Speltz Elizabeth B,Zalatan Jesse G
Cell systems
Scaffold proteins are thought to promote signaling specificity by accelerating reactions between bound kinase and substrate proteins. To test the long-standing hypothesis that the scaffold protein Axin accelerates glycogen synthase kinase 3β (GSK3β)-mediated phosphorylation of β-catenin in the Wnt signaling network, we measured GSK3β reaction rates with multiple substrates in a minimal, biochemically reconstituted system. We observed an unexpectedly small, ∼2-fold Axin-mediated rate increase for the β-catenin reaction when measured in isolation. In contrast, when both β-catenin and non-Wnt pathway substrates are present, Axin accelerates the β-catenin reaction by preventing competition with alternative substrates. At high competitor concentrations, Axin produces >10-fold rate effects. Thus, while Axin alone does not markedly accelerate the β-catenin reaction, in physiological settings where multiple GSK3β substrates are present, Axin may promote signaling specificity by suppressing interactions with competing, non-Wnt pathway targets. This mechanism for scaffold-mediated control of competition enables a shared kinase to perform distinct functions in multiple signaling networks.
10.1016/j.cels.2020.05.002
Roles of Axin in the Wnt signalling pathway.
Kikuchi A
Cellular signalling
The Wnt signalling pathway is conserved in various species from worms to mammals, and plays important roles in development, cellular proliferation, and differentiation. The molecular mechanisms by which the Wnt signal regulates cellular functions are becoming increasingly well understood. Wnt stabilizes cytoplasmic beta-catenin, which stimulates the expression of genes including c-myc, c-jun, fra-1, and cyclin D1. Axin, newly recognized as a component of the Wnt signalling pathway, negatively regulates this pathway. Other components of the Wnt signalling pathway, including Dvl, glycogen synthase kinase-3beta, beta-catenin, and adenomatous polyposis coli, interact with Axin, and the phosphorylation and stability of beta-catenin are regulated in the Axin complex. Thus, Axin acts as a scaffold protein in the Wnt signalling pathway, thereby regulating cellular functions.
SUMOylation of RNF146 results in Axin degradation and activation of Wnt/β-catenin signaling to promote the progression of hepatocellular carcinoma.
Oncogene
Aberrant SUMOylation contributes to the progression of hepatocellular carcinoma (HCC), yet the molecular mechanisms have not been well elucidated. RING-type E3 ubiquitin ligase RNF146 is a key regulator of the Wnt/β-catenin signaling pathway, which is frequently hyperactivated in HCC. Here, it is identified that RNF146 can be modified by SUMO3. By mutating all lysines in RNF146, we found that K19, K61, K174 and K175 are the major sites for SUMOylation. UBC9/PIAS3/MMS21 and SENP1/2/6 mediated the conjugation and deconjugation of SUMO3, respectively. Furthermore, SUMOylation of RNF146 promoted its nuclear localization, while deSUMOylation induced its cytoplasmic localization. Importantly, SUMOylation promotes the association of RNF146 with Axin to accelerate the ubiquitination and degradation of Axin. Intriguingly, only UBC9/PIAS3 and SENP1 can act at K19/K175 in RNF146 and affect its role in regulating the stability of Axin. In addition, inhibiting RNF146 SUMOylation suppressed the progression of HCC both in vitro and in vivo. And, patients with higher expression of RNF146 and UBC9 have the worst prognosis. Taken together, we conclude that RNF146 SUMOylation at K19/K175 promotes its association with Axin and accelerates Axin degradation, thereby enhancing β-catenin signaling and contributing to cancer progression. Our findings reveal that RNF146 SUMOylation is a potential therapeutic target in HCC.
10.1038/s41388-023-02689-4
The Axin scaffold protects the kinase GSK3β from cross-pathway inhibition.
eLife
Multiple signaling pathways regulate the kinase GSK3β by inhibitory phosphorylation at Ser9, which then occupies the GSK3β priming pocket and blocks substrate binding. Since this mechanism should affect GSK3β activity toward all primed substrates, it is unclear why Ser9 phosphorylation does not affect other GSK3β-dependent pathways, such as Wnt signaling. We used biochemical reconstitution and cell culture assays to evaluate how Wnt-associated GSK3β is insulated from cross-activation by other signals. We found that the Wnt-specific scaffold protein Axin allosterically protects GSK3β from phosphorylation at Ser9 by upstream kinases, which prevents accumulation of pS9-GSK3β in the Axin•GSK3β complex. Scaffold proteins that protect bound proteins from alternative pathway reactions could provide a general mechanism to insulate signaling pathways from improper crosstalk.
10.7554/eLife.85444
The links between axin and carcinogenesis.
Salahshor S,Woodgett J R
Journal of clinical pathology
The products of the two mammalian Axin genes (Axin1 and its homologue Axin2) are essential for the degradation of beta catenin, a component of Wnt signalling that is frequently dysregulated in cancer cells. Axin is a multidomain scaffold protein that has many functions in biological signalling pathways. Overexpression of mutant [corrected] axin results in axis duplication in mouse embryos. Wnt signalling activity determines dorsal-ventral axis formation in vertebrates, implicating axin as a negative regulator of this signalling pathway. In addition, Wnts modulate pattern formation and the morphogenesis of most organs by influencing and controlling cell proliferation, motility, and fate. Defects in different components of the Wnt signalling pathway promote tumorigenesis and tumour progression. Recent biochemical studies of axins indicate that these molecules are the primary limiting components of this pathway. This review explores the intriguing connections between defects in axin function and human diseases.
10.1136/jcp.2003.009506
β-Catenin signaling in hepatocellular carcinoma.
Xu Chuanrui,Xu Zhong,Zhang Yi,Evert Matthias,Calvisi Diego F,Chen Xin
The Journal of clinical investigation
Deregulated Wnt/β-catenin signaling is one of the main genetic alterations in human hepatocellular carcinoma (HCC). Comprehensive genomic analyses have revealed that gain-of-function mutation of CTNNB1, which encodes β-catenin, and loss-of-function mutation of AXIN1 occur in approximately 35% of human HCC samples. Human HCCs with activation of the Wnt/β-catenin pathway demonstrate unique gene expression patterns and pathological features. Activated Wnt/β-catenin synergizes with multiple signaling cascades to drive HCC formation, and it functions through its downstream effectors. Therefore, strategies targeting Wnt/β-catenin have been pursued as possible therapeutics against HCC. Here, we review the genetic alterations and oncogenic roles of aberrant Wnt/β-catenin signaling during hepatocarcinogenesis. In addition, we discuss the implication of this pathway in HCC diagnosis, classification, and personalized treatment.
10.1172/JCI154515