Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors

Bon Kyoung Koo, Maureen Spit, Ingrid Jordens, Low Teck Yew, Daniel E. Stange, Marc Van De Wetering, Johan H. Van Es, Shabaz Mohammed, Albert J R Heck, Madelon M. Maurice, Hans Clevers

Research output: Contribution to journalArticle

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Abstract

LGR5 + stem cells reside at crypt bottoms, intermingled with Paneth cells that provide Wnt, Notch and epidermal growth factor signals. Here we find that the related RNF43 and ZNRF3 transmembrane E3 ubiquitin ligases are uniquely expressed in LGR5 + stem cells. Simultaneous deletion of the two genes encoding these proteins in the intestinal epithelium of mice induces rapidly growing adenomas containing high numbers of Paneth and LGR5 + stem cells. In vitro, growth of organoids derived from these adenomas is arrested when Wnt secretion is inhibited, indicating a dependence of the adenoma stem cells on Wnt produced by adenoma Paneth cells. In the HEK293T human cancer cell line, expression of RNF43 blocks Wnt responses and targets surface-expressed frizzled receptors to lysosomes. In the RNF43-mutant colorectal cancer cell line HCT116, reconstitution of RNF43 expression removes its response to exogenous Wnt. We conclude that RNF43 and ZNRF3 reduce Wnt signals by selectively ubiquitinating frizzled receptors, thereby targeting these Wnt receptors for degradation.

Original languageEnglish
Pages (from-to)665-669
Number of pages5
JournalNature
Volume488
Issue number7413
DOIs
Publication statusPublished - 30 Aug 2012
Externally publishedYes

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Wnt Receptors
Ubiquitin-Protein Ligases
Endocytosis
Adenoma
Stem Cells
Frizzled Receptors
Paneth Cells
Neoplasms
Organoids
Cell Line
Intestinal Mucosa
Lysosomes
Epidermal Growth Factor
Colorectal Neoplasms
Growth
Proteins

ASJC Scopus subject areas

  • General

Cite this

Koo, B. K., Spit, M., Jordens, I., Teck Yew, L., Stange, D. E., Van De Wetering, M., ... Clevers, H. (2012). Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors. Nature, 488(7413), 665-669. https://doi.org/10.1038/nature11308

Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors. / Koo, Bon Kyoung; Spit, Maureen; Jordens, Ingrid; Teck Yew, Low; Stange, Daniel E.; Van De Wetering, Marc; Van Es, Johan H.; Mohammed, Shabaz; Heck, Albert J R; Maurice, Madelon M.; Clevers, Hans.

In: Nature, Vol. 488, No. 7413, 30.08.2012, p. 665-669.

Research output: Contribution to journalArticle

Koo, BK, Spit, M, Jordens, I, Teck Yew, L, Stange, DE, Van De Wetering, M, Van Es, JH, Mohammed, S, Heck, AJR, Maurice, MM & Clevers, H 2012, 'Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors', Nature, vol. 488, no. 7413, pp. 665-669. https://doi.org/10.1038/nature11308
Koo BK, Spit M, Jordens I, Teck Yew L, Stange DE, Van De Wetering M et al. Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors. Nature. 2012 Aug 30;488(7413):665-669. https://doi.org/10.1038/nature11308
Koo, Bon Kyoung ; Spit, Maureen ; Jordens, Ingrid ; Teck Yew, Low ; Stange, Daniel E. ; Van De Wetering, Marc ; Van Es, Johan H. ; Mohammed, Shabaz ; Heck, Albert J R ; Maurice, Madelon M. ; Clevers, Hans. / Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors. In: Nature. 2012 ; Vol. 488, No. 7413. pp. 665-669.
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