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

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.

• Authors: Bon-Kyoung Koo, Maureen Spit, Ingrid Jordens, Teck Y Low, Daniel E Stange, Marc van de Wetering, Johan H van Es, Shabaz Mohammed, Albert J R Heck, Madelon M Maurice, Hans Clevers
• Journal: Nature (Nature) Vol. 488 Issue 7413 Pg. 665-9 (Aug 30 2012) ISSN: 1476-4687 [Electronic] England
• PMID: 22895187 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• 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)