UCHL5 controls β-catenin destruction complex function through Axin1 regulation

Han, Wonhee; Koo, Youngmu; Chaieb, Leila; Keum, Byeong-Rak; Han, Jin‐Kwan

doi:10.1038/s41598-022-07642-1

Cited by 11 publications

(4 citation statements)

References 29 publications

(69 reference statements)

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“…Full length of mouse Axin1 and human AXIN1 constructs were kindly provided by Dr. Frank Costantini. The -catenin CTNNB1 constructs were obtained as described previously 50 . Point and deletion mutagenesis were used to generate catalytic-dead (D82A, H115Q) and deletion ( DYFL) mutants of ppp4c , and the truncated forms (1–433, 434–826, 65–826, 65–545, and 396–826) of mouse Axin1 .…”

Section: Methodsmentioning

confidence: 99%

Identification of protein phosphatase 4 catalytic subunit as a Wnt promoting factor in pan-cancer and Xenopus early embryogenesis

Wang

Han

Yun

et al. 2023

Sci Rep

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Protein Phosphatase 4 Catalytic Subunit (PPP4C) is an evolutionarily conserved protein involved in multiple biological and pathological events, including embryogenesis, organogenesis, cellular homeostasis, and oncogenesis. However, the detailed mechanisms underlying these processes remain largely unknown. Thus, we investigated the potential correlation between PPP4C and biological processes (BPs) and canonical Wnt signaling using pan-cancer analysis and Xenopus laevis (X. laevis) embryo model. Our results indicate that PPP4C is a potential biomarker for specific cancer types due to its high diagnostic accuracy and significant prognostic correlation. Furthermore, in multiple cancer types, PPP4C-related differentially expressed genes (DEGs) were significantly enriched in pattern specification, morphogenesis, and canonical Wnt activation. Consistently, perturbation of Ppp4c in X. laevis embryos interfered with normal embryogenesis and canonical Wnt responses. Moreover, biochemical analysis of X. laevis embryos demonstrated that both endogenous and exogenous Ppp4c negatively regulated AXIN1 (Wnt inhibitor) abundance. This study provides novel insights into PPP4C roles in pattern specification and Wnt activation. The similarities in BPs and Wnt signaling regulation regarding PPP4C support the intrinsic link between tumorigenesis and early embryogenesis.

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Section: Methodsmentioning

confidence: 99%

Identification of protein phosphatase 4 catalytic subunit as a Wnt promoting factor in pan-cancer and Xenopus early embryogenesis

Wang

Han

Yun

et al. 2023

Sci Rep

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“…We generated stable HeLa cell lines which expressed b-catenin* and the aromatic mutants from a DOX-inducible expression cassette via lentiviral transduction. We chose to assay the Wnt target genes Axin2 and Sp5 as they are strongly activated by Wnt signaling in HeLa cells [36,37]. qPCR analysis of HeLa cells expressing b-catenin* and the aromatic mutants indicates that the relationship between aromatic amino acid residues and gene regulation is slightly more complex than the reporter activity (Fig 4A).…”

Section: Aromatic Amino Acid Residues Within B-catenin's Idrs Are Cri...mentioning

confidence: 99%

β-catenin-mediated activation of Wnt target genes utilizes a biomolecular condensate-dependent mechanism

Stewart,

Goodman,

Tran

et al. 2023

Preprint

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The Wnt/beta-catenin signaling pathway plays numerous, essential roles in animal development and tissue/stem cell maintenance. The activation of genes regulated by Wnt/beta-catenin signaling requires the nuclear accumulation of beta-catenin, a transcriptional co-activator. beta-catenin is recruited to many Wnt-regulated enhancers through direct binding to T-cell factor/Lymphoid enhancer factor (TCF/LEF) family transcription factors. beta-catenin has previously been reported to form phase-separated biomolecular condensates (BMCs), which was implicated as a component of beta-catenin's mechanism of action. This function required aromatic amino acid residues in the intrinsically disordered regions (IDRs) at the N- and C-termini of the protein. In this report, we further explore a role for beta-catenin BMCs in Wnt target gene regulation. We find that beta-catenin BMCs are miscible with LEF1 BMCs in vitro. We characterized a panel of beta-catenin mutants with different combinations of aromatic residue mutations in human cell culture and Drosophila melanogaster. Our data support a model in which aromatic residues across both IDRs contribute to BMC formation in vitro and signaling activity in vivo. Although different Wnt targets have different sensitivities to loss of beta-catenin's aromatic residues, the activation of every target examined was compromised by aromatic substitution. These mutants are not defective in nuclear import, and residues in the N-terminal IDR with no previously known role in signaling are clearly required for the activation of various Wnt readouts. Consistent with this, deletion of the N-terminal IDR results in a loss of signaling activity, which can be rescued by the addition of heterologous IDRs enriched in aromatic residues. Overall, our work supports a model in which the ability of beta-catenin to form biomolecular condensates in the nucleus is tightly linked to its function as a transcriptional co-regulator.

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“…These stabilizing influences have been documented through various mechanisms. Reports have indicated that deubiquitinating enzymes, including USP7 [ 69 ], USP44 [ 70 ], USP49 [ 71 ], and UCHL5 [ 72 ], can reduce the ubiquitination of AXIN1, thereby hampering WNT/β-catenin signaling. DAB2 contributes to an increase in the protein level of AXIN1 by impeding the dephosphorylation of PP1 on AXIN1 [ 73 , 74 ].…”

Section: Introductionmentioning

confidence: 99%

The scaffold protein AXIN1: gene ontology, signal network, and physiological function

Qiu,

Sun,

Ning

et al. 2024

Cell Commun Signal

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AXIN1, has been initially identified as a prominent antagonist within the WNT/β-catenin signaling pathway, and subsequently unveiled its integral involvement across a diverse spectrum of signaling cascades. These encompass the WNT/β-catenin, Hippo, TGFβ, AMPK, mTOR, MAPK, and antioxidant signaling pathways. The versatile engagement of AXIN1 underscores its pivotal role in the modulation of developmental biological signaling, maintenance of metabolic homeostasis, and coordination of cellular stress responses. The multifaceted functionalities of AXIN1 render it as a compelling candidate for targeted intervention in the realms of degenerative pathologies, systemic metabolic disorders, cancer therapeutics, and anti-aging strategies. This review provides an intricate exploration of the mechanisms governing mammalian AXIN1 gene expression and protein turnover since its initial discovery, while also elucidating its significance in the regulation of signaling pathways, tissue development, and carcinogenesis. Furthermore, we have introduced the innovative concept of the AXIN1-Associated Phosphokinase Complex (AAPC), where the scaffold protein AXIN1 assumes a pivotal role in orchestrating site-specific phosphorylation modifications through interactions with various phosphokinases and their respective substrates.

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UCHL5 controls β-catenin destruction complex function through Axin1 regulation

Cited by 11 publications

References 29 publications

Identification of protein phosphatase 4 catalytic subunit as a Wnt promoting factor in pan-cancer and Xenopus early embryogenesis

Identification of protein phosphatase 4 catalytic subunit as a Wnt promoting factor in pan-cancer and Xenopus early embryogenesis

β-catenin-mediated activation of Wnt target genes utilizes a biomolecular condensate-dependent mechanism

The scaffold protein AXIN1: gene ontology, signal network, and physiological function

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