NEDD4 and NEDD4L regulate Wnt signalling and intestinal stem cell priming by degrading LGR5 receptor

Novellasdemunt, Laura; Kucharská, Anna; Jamieson, Cara; Prange‐Barczynska, Maria; Baulies, Anna; Antas, Pedro; Vaart, Jelte van der; Gehart, Helmuth; Maurice, Madelon M.

doi:10.15252/embj.2019102771

Cited by 69 publications

(44 citation statements)

References 56 publications

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“…We then turned to investigating O-GalNAc glycosylation in a multicellular model system. Intestinal organoids are instrumental in understanding some of the key concepts of bowel cancer formation as well as normal gut development and homeostasis ( 48 – 52 ). Production of O-GalNAc glycans in such systems is often probed by either backbone-directed antibodies or lectins ( 53 , 54 ).…”

Section: Resultsmentioning

confidence: 99%

Metabolic precision labeling enables selective probing of O-linked N -acetylgalactosamine glycosylation

Debets

Tastan

Wisnovsky

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Protein glycosylation events that happen early in the secretory pathway are often dysregulated during tumorigenesis. These events can be probed, in principle, by monosaccharides with bioorthogonal tags that would ideally be specific for distinct glycan subtypes. However, metabolic interconversion into other monosaccharides drastically reduces such specificity in the living cell. Here, we use a structure-based design process to develop the monosaccharide probe N-(S)-azidopropionylgalactosamine (GalNAzMe) that is specific for cancer-relevant Ser/Thr(O)–linked N-acetylgalactosamine (GalNAc) glycosylation. By virtue of a branched N-acylamide side chain, GalNAzMe is not interconverted by epimerization to the corresponding N-acetylglucosamine analog by the epimerase N-acetylgalactosamine–4-epimerase (GALE) like conventional GalNAc–based probes. GalNAzMe enters O-GalNAc glycosylation but does not enter other major cell surface glycan types including Asn(N)-linked glycans. We transfect cells with the engineered pyrophosphorylase mut-AGX1 to biosynthesize the nucleotide-sugar donor uridine diphosphate (UDP)-GalNAzMe from a sugar-1-phosphate precursor. Tagged with a bioorthogonal azide group, GalNAzMe serves as an O-glycan–specific reporter in superresolution microscopy, chemical glycoproteomics, a genome-wide CRISPR-knockout (CRISPR-KO) screen, and imaging of intestinal organoids. Additional ectopic expression of an engineered glycosyltransferase, “bump-and-hole” (BH)–GalNAc-T2, boosts labeling in a programmable fashion by increasing incorporation of GalNAzMe into the cell surface glycoproteome. Alleviating the need for GALE-KO cells in metabolic labeling experiments, GalNAzMe is a precision tool that allows a detailed view into the biology of a major type of cancer-relevant protein glycosylation.

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Section: Resultsmentioning

confidence: 99%

Metabolic precision labeling enables selective probing of O-linked N -acetylgalactosamine glycosylation

Debets

Tastan

Wisnovsky

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Our analysis indicates that LGR5 expression is positively correlated with AXIN2, and particularly with TCF7 in normal tissue (Figure 3); also, the related LGR4 is even more strongly correlated with TCF7L2 expression (Table 3, Supplementary Table S2D). NEDD4 and NEDD4L were recently identified as regulators of LGR5 protein degradation [60]. In our analysis, NEDD4 expression (but not NEDD4L) is conspicuous, initially for being differentially correlated with AXIN2 expression, negatively in normal tissue and positively in cancer tissue; and additionally, for being positively correlated with TCF7L1 in normal tissue, which is opposite to AXIN2, but being positively correlated with TCF7 expression in tumor tissue, as AXIN2.…”

Section: Feedback Regulation Of Wnt Signaling Components At the Cell Membranementioning

confidence: 62%

Diverse LEF/TCF Expression in Human Colorectal Cancer Correlates with Altered Wnt-Regulated Transcriptome in a Meta-Analysis of Patient Biopsies

Mayer

Giclais

Alsehly

et al. 2020

Genes

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Aberrantly activated Wnt signaling causes cellular transformation that can lead to human colorectal cancer. Wnt signaling is mediated by Lymphoid Enhancer Factor/T-Cell Factor (LEF/TCF) DNA-binding factors. Here we investigate whether altered LEF/TCF expression is conserved in human colorectal tumor sample and may potentially be correlated with indicators of cancer progression. We carried out a meta-analysis of carefully selected publicly available gene expression data sets with paired tumor biopsy and adjacent matched normal tissues from colorectal cancer patients. Our meta-analysis confirms that among the four human LEF/TCF genes, LEF1 and TCF7 are preferentially expressed in tumor biopsies, while TCF7L2 and TCF7L1 in normal control tissue. We also confirm positive correlation of LEF1 and TCF7 expression with hallmarks of active Wnt signaling (i.e., AXIN2 and LGR5). We are able to correlate differential LEF/TCF gene expression with distinct transcriptomes associated with cell adhesion, extracellular matrix organization, and Wnt receptor feedback regulation. We demonstrate here in human colorectal tumor sample correlation of altered LEF/TCF gene expression with quantitatively and qualitatively different transcriptomes, suggesting LEF/TCF-specific transcriptional regulation of Wnt target genes relevant for cancer progression and survival. This bioinformatics analysis provides a foundation for future more detailed, functional, and molecular analyses aimed at dissecting such functional differences.

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“…2c , including 224 intergenic CpG sites, 108 promoter CpG sites, 71 intron CpG sites, 12 exons CpG sites), where the enhancers and regulatory elements are located. Gene ontology analysis of the annotated gene targets that gained DNA methylation in KO cells revealed that these targets were most significantly enriched for the functional annotation group involved in regulation of neuron differentiation process (Supplementary Data 1 ), where several of these annotated genes, including Asap1, Robo2, Nedd4l , have been known to be involved in negative regulation of mammary stem cell and stem cell differentiation 23 – 25 (Supplementary Data 1 ).…”

Section: Resultsmentioning

confidence: 99%

TET2 directs mammary luminal cell differentiation and endocrine response

Kim

Zhang

et al. 2020

Nat Commun

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Epigenetic regulation plays an important role in governing stem cell fate and tumorigenesis. Lost expression of a key DNA demethylation enzyme TET2 is associated with human cancers and has been linked to stem cell traits in vitro; however, whether and how TET2 regulates mammary stem cell fate and mammary tumorigenesis in vivo remains to be determined. Here, using our recently established mammary specific Tet2 deletion mouse model, the data reveals that TET2 plays a pivotal role in mammary gland development and luminal lineage commitment. We show that TET2 and FOXP1 form a chromatin complex that mediates demethylation of ESR1, GATA3, and FOXA1, three key genes that are known to coordinately orchestrate mammary luminal lineage specification and endocrine response, and also are often silenced by DNA methylation in aggressive breast cancers. Furthermore, Tet2 deletion-PyMT breast cancer mouse model exhibits enhanced mammary tumor development with deficient ERα expression that confers tamoxifen resistance in vivo. As a result, this study elucidates a role for TET2 in governing luminal cell differentiation and endocrine response that underlies breast cancer resistance to anti-estrogen treatments.

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NEDD4 and NEDD4L regulate Wnt signalling and intestinal stem cell priming by degrading LGR5 receptor

Cited by 69 publications

References 56 publications

Metabolic precision labeling enables selective probing of O-linked N -acetylgalactosamine glycosylation

Metabolic precision labeling enables selective probing of O-linked N -acetylgalactosamine glycosylation

Diverse LEF/TCF Expression in Human Colorectal Cancer Correlates with Altered Wnt-Regulated Transcriptome in a Meta-Analysis of Patient Biopsies

TET2 directs mammary luminal cell differentiation and endocrine response

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