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PMID: 22895187 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Nature ·Vol. 488 ·No. 7413 ·2012-08-30 ·Pages 665-9

Koo BK, Spit M, Jordens I, Low TY, Stange DE, van de Wetering M, van Es JH, Mohammed S, Heck AJ, Maurice MM, Clevers H

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.

MeSH Terms

Adenoma/metabolism,pathology Animals Cell Proliferation Colorectal Neoplasms/metabolism,pathology DNA-Binding Proteins/deficiency,genetics,metabolism Endocytosis Frizzled Receptors/metabolism HEK293 Cells Humans Lysosomes/metabolism Mice Oncogene Proteins/deficiency,genetics,metabolism Organoids/cytology,metabolism,pathology Paneth Cells/metabolism,pathology Receptors, G-Protein-Coupled/genetics,metabolism Receptors, Wnt/antagonists & inhibitors,metabolism Stem Cells/cytology,enzymology,metabolism Tumor Suppressor Proteins/deficiency,genetics,metabolism Ubiquitin/metabolism Ubiquitin-Protein Ligases/deficiency,genetics,metabolism Ubiquitination Wnt Signaling Pathway/drug effects beta Catenin/metabolism

Chemicals

DNA-Binding Proteins Frizzled Receptors Lgr5 protein, mouse Oncogene Proteins Receptors, G-Protein-Coupled Receptors, Wnt Tumor Suppressor Proteins Ubiquitin beta Catenin RNF43 protein, human RNF43 protein, mouse Ubiquitin-Protein Ligases Znrf3 protein, mouse

Authors & Affiliations

11 authors, click to expand affiliations / ORCID

Koo Bon-Kyoung

Hubrecht Institute, KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, The Netherlands.

Spit Maureen

Jordens Ingrid

Low Teck Y

Stange Daniel E

van de Wetering Marc

van Es Johan H

Mohammed Shabaz

Heck Albert J R

Maurice Madelon M

Clevers Hans

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Article Info

Journal

Nature

Abbr.

Nature

ISSN

1476-4687

DOI

10.1038/nature11308

Published

2012-08-30

Pages

665-9

Language

English

Region

England

NLM ID

0410462

Subset

Databases

GEO

GSE36497

Corrections

CommentIn

PMID: 23058807

External Links

PubMed source DOI: 10.1038/nature11308 View journal details

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

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