SH3BP4 Regulates Intestinal Stem Cells and Tumorigenesis by Modulating β-Catenin Nuclear Localization

Antas, Pedro; Novellasdemunt, Laura; Kucharská, Anna; Massie, Isobel; Carvalho, Joana; Oukrif, Dahmane; Nye, Emma; Novelli, Marco; Li, Vivian

doi:10.1016/j.celrep.2019.01.110

Cited by 23 publications

(18 citation statements)

References 31 publications

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“…Previous studies have identified several crypt-expressing Wnt inhibitors such as AXIN2, RNF43 and SH3BP4 that are involved in CRC development by targeting Wnt signalling pathway at different subcellular levels (Cancer Genome Atlas, 2012;Giannakis et al, 2014, Yan et al, 2017aAntas et al, 2019). In this study, we uncover a new crypt-expressing Wnt regulator NEDD4 that targets two Wnt pathway components LGR4/5 and DVL2 to maintain ISC homeostasis and suppress intestinal tumorigenesis ( Fig 7D).…”

Section: Discussionmentioning

confidence: 62%

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

et al. 2019

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The intestinal stem cell (ISC) marker LGR5 is a receptor for Rspondin (RSPO) that functions to potentiate Wnt signalling in the proliferating crypt. It has been recently shown that Wnt plays a priming role for ISC self-renewal by inducing RSPO receptor LGR5 expression. Despite its pivotal role in homeostasis, regeneration and cancer, little is known about the post-translational regulation of LGR5. Here, we show that the HECT-domain E3 ligases NEDD4 and NEDD4L are expressed in the crypt stem cell regions and regulate ISC priming by degrading LGR receptors. Loss of Nedd4 and Nedd4l enhances ISC proliferation, increases sensitivity to RSPO stimulation and accelerates tumour development in Apc min mice with increased numbers of high-grade adenomas. Mechanistically, we find that both NEDD4 and NEDD4L negatively regulate Wnt/bcatenin signalling by targeting LGR5 receptor and DVL2 for proteasomal and lysosomal degradation. Our findings unveil the previously unreported post-translational control of LGR receptors via NEDD4/NEDD4L to regulate ISC priming. Inactivation of NEDD4 and NEDD4L increases Wnt activation and ISC numbers, which subsequently enhances tumour predisposition and progression.

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Section: Discussionmentioning

confidence: 62%

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

et al. 2019

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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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“…Histology revealed moderate osteoarthritis with articular cartilage fibrillations and vertical clefts over <25% of the articular surface extending to the calcified cartilage beneath (OARSI grade 3) (Figure 4, Supplementary Figure 4 and Supplementary Table 3). Sh3bp4 is a poorly characterized SH3 domain binding protein involved in transferrin receptor (TfR) internalization 43 , fibroblast growth factor receptor (FGFR) trafficking 44 , mammalian target of rapamycin (mTOR) signalling 45 and inhibition of the Wnt pathway 46 . SH3BP4 has not been associated with osteoarthritis in GWAS.…”

Section: Early Onset Osteoarthritis In Bhlhe40 -/And Sh3pb4 -/Mutant mentioning

confidence: 99%

Accelerating functional gene discovery in osteoarthritis

Butterfield

Curry

Steinberg

et al. 2019

Preprint

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Osteoarthritis causes debilitating pain and disability, resulting in a huge socioeconomic burden, yet no drugs are available that prevent disease onset or progression. Here, we develop, validate and use rapid-throughput imaging techniques to identify abnormal joint phenotypes in unselected mutant mice generated by the International Knockout Mouse Consortium. We identify 14 genes with functional involvement in osteoarthritis pathogenesis, including the homeobox gene Pitx1, and functionally characterize 6 candidate human osteoarthritis genes in mouse models. We demonstrate sensitivity of the methods by identifying age-related degenerative joint damage in wild-type mice. Finally, we generate mutant mice with an osteoarthritis-associated polymorphism in the Dio2 gene by Crispr/Cas9 genome editing and demonstrate a protective role in disease onset with public health implications. This expanding resource of unselected mutant mice will transform the field by accelerating functional gene discovery in osteoarthritis and offering unanticipated drug discovery opportunities for this common and incapacitating chronic disease.

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SH3BP4 Regulates Intestinal Stem Cells and Tumorigenesis by Modulating β-Catenin Nuclear Localization

Cited by 23 publications

References 31 publications

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

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

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

Accelerating functional gene discovery in osteoarthritis

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