RNF43 R117fs mutant positively regulates Wnt/β-catenin signaling by failing to internalize FZD expressed on the cell surface
Abstract RING finger protein 43 (RNF43) encodes the transmembrane E3 ubiquitin ligase, which targets the Wnt receptor Frizzled (FZD). RNF43 mutations have been discovered in various human cancers including colon, pancreatic, stomach, ovarian, and liver cancers. Functional studies on RNF43 missense m...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-04-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-10868-8 |
| _version_ | 1811289434092470272 |
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| author | A-Ri Cho Hee Jung Sul Yoo Jin Kim Bohyun Kim Dae Young Zang |
| author_facet | A-Ri Cho Hee Jung Sul Yoo Jin Kim Bohyun Kim Dae Young Zang |
| author_sort | A-Ri Cho |
| collection | DOAJ |
| description | Abstract RING finger protein 43 (RNF43) encodes the transmembrane E3 ubiquitin ligase, which targets the Wnt receptor Frizzled (FZD). RNF43 mutations have been discovered in various human cancers including colon, pancreatic, stomach, ovarian, and liver cancers. Functional studies on RNF43 missense mutations have shown that they negatively regulate Wnt signaling; however, there are few functional studies on RNF43 frameshift mutations. In this study, we showed that R117fs and P441fs mutants enhanced Wnt/β-catenin signaling, whereas Q409fs and G659fs mutants retained the ability to suppress Wnt/β-catenin signaling. Specifically, R117fs was unable to ubiquitinate FZD5 due to lack of the RING domain, although it was able to interact with FZD5. Immunofluorescence showed that R117fs failed to internalize FZD5 expressed on the cell surface. We also showed that LGK974, a potent Wnt inhibitor, decreased the Wnt/β-catenin activity by R117fs and P441fs mutations. Together, these results demonstrate that RNF43 frameshift mutations retain normal functionality; thus, targeted anti-cancer therapy can be developed according to the mutation type of RNF43. |
| first_indexed | 2024-04-13T03:54:44Z |
| format | Article |
| id | doaj.art-8f4ad4a2e7844b7d9f77ab6c70cc1969 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-13T03:54:44Z |
| publishDate | 2022-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-8f4ad4a2e7844b7d9f77ab6c70cc19692022-12-22T03:03:41ZengNature PortfolioScientific Reports2045-23222022-04-011211910.1038/s41598-022-10868-8RNF43 R117fs mutant positively regulates Wnt/β-catenin signaling by failing to internalize FZD expressed on the cell surfaceA-Ri Cho0Hee Jung Sul1Yoo Jin Kim2Bohyun Kim3Dae Young Zang4Hallym Translational Research Institute, Hallym University Sacred Heart HospitalHallym Translational Research Institute, Hallym University Sacred Heart HospitalHallym Translational Research Institute, Hallym University Sacred Heart HospitalHallym Translational Research Institute, Hallym University Sacred Heart HospitalHallym Translational Research Institute, Hallym University Sacred Heart HospitalAbstract RING finger protein 43 (RNF43) encodes the transmembrane E3 ubiquitin ligase, which targets the Wnt receptor Frizzled (FZD). RNF43 mutations have been discovered in various human cancers including colon, pancreatic, stomach, ovarian, and liver cancers. Functional studies on RNF43 missense mutations have shown that they negatively regulate Wnt signaling; however, there are few functional studies on RNF43 frameshift mutations. In this study, we showed that R117fs and P441fs mutants enhanced Wnt/β-catenin signaling, whereas Q409fs and G659fs mutants retained the ability to suppress Wnt/β-catenin signaling. Specifically, R117fs was unable to ubiquitinate FZD5 due to lack of the RING domain, although it was able to interact with FZD5. Immunofluorescence showed that R117fs failed to internalize FZD5 expressed on the cell surface. We also showed that LGK974, a potent Wnt inhibitor, decreased the Wnt/β-catenin activity by R117fs and P441fs mutations. Together, these results demonstrate that RNF43 frameshift mutations retain normal functionality; thus, targeted anti-cancer therapy can be developed according to the mutation type of RNF43.https://doi.org/10.1038/s41598-022-10868-8 |
| spellingShingle | A-Ri Cho Hee Jung Sul Yoo Jin Kim Bohyun Kim Dae Young Zang RNF43 R117fs mutant positively regulates Wnt/β-catenin signaling by failing to internalize FZD expressed on the cell surface Scientific Reports |
| title | RNF43 R117fs mutant positively regulates Wnt/β-catenin signaling by failing to internalize FZD expressed on the cell surface |
| title_full | RNF43 R117fs mutant positively regulates Wnt/β-catenin signaling by failing to internalize FZD expressed on the cell surface |
| title_fullStr | RNF43 R117fs mutant positively regulates Wnt/β-catenin signaling by failing to internalize FZD expressed on the cell surface |
| title_full_unstemmed | RNF43 R117fs mutant positively regulates Wnt/β-catenin signaling by failing to internalize FZD expressed on the cell surface |
| title_short | RNF43 R117fs mutant positively regulates Wnt/β-catenin signaling by failing to internalize FZD expressed on the cell surface |
| title_sort | rnf43 r117fs mutant positively regulates wnt β catenin signaling by failing to internalize fzd expressed on the cell surface |
| url | https://doi.org/10.1038/s41598-022-10868-8 |
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