SCFβ-TRCP E3 ubiquitin ligase targets the tumor suppressor ZNRF3 for ubiquitination and degradation
Abstract Wnt signaling has emerged as a major regulator of tissue development by governing the self-renewal and maintenance of stem cells in most tissue types. As a key upstream regulator of the Wnt pathway, the transmembrane E3 ligase ZNRF3 has recently been established to play a role in negative r...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Oxford University Press
2018-03-01
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| Series: | Protein & Cell |
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| Online Access: | http://link.springer.com/article/10.1007/s13238-018-0510-2 |
| _version_ | 1797706061930561536 |
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| author | Yanpeng Ci Xiaoning Li Maorong Chen Jiateng Zhong Brian J. North Hiroyuki Inuzuka Xi He Yu Li Jianping Guo Xiangpeng Dai |
| author_facet | Yanpeng Ci Xiaoning Li Maorong Chen Jiateng Zhong Brian J. North Hiroyuki Inuzuka Xi He Yu Li Jianping Guo Xiangpeng Dai |
| author_sort | Yanpeng Ci |
| collection | DOAJ |
| description | Abstract Wnt signaling has emerged as a major regulator of tissue development by governing the self-renewal and maintenance of stem cells in most tissue types. As a key upstream regulator of the Wnt pathway, the transmembrane E3 ligase ZNRF3 has recently been established to play a role in negative regulation of Wnt signaling by targeting Frizzled (FZD) receptor for ubiquitination and degradation. However, the upstream regulation of ZNRF3, in particular the turnover of ZNRF3, is still unclear. Here we report that ZNRF3 is accumulated in the presence of proteasome inhibitor treatment independent of its E3-ubiquitin ligase activity. Furthermore, the Cullin 1-specific SCF complex containing β-TRCP has been identified to directly interact with and ubiquitinate ZNRF3 thereby regulating its protein stability. Similar with the degradation of β-catenin by β-TRCP, ZNRF3 is ubiquitinated by β-TRCP in both CKI-phosphorylation- and degron-dependent manners. Thus, our findings not only identify a novel substrate for β-TRCP oncogenic regulation, but also highlight the dual regulation of Wnt signaling by β-TRCP in a context-dependent manner where β-TRCP negatively regulates Wnt signaling by targeting β-catenin, and positively regulates Wnt signaling by targeting ZNRF3. |
| first_indexed | 2024-03-12T05:46:38Z |
| format | Article |
| id | doaj.art-93722ce5a2c342c2829a17d45616a3ea |
| institution | Directory Open Access Journal |
| issn | 1674-800X 1674-8018 |
| language | English |
| last_indexed | 2024-03-12T05:46:38Z |
| publishDate | 2018-03-01 |
| publisher | Oxford University Press |
| record_format | Article |
| series | Protein & Cell |
| spelling | doaj.art-93722ce5a2c342c2829a17d45616a3ea2023-09-03T05:36:40ZengOxford University PressProtein & Cell1674-800X1674-80182018-03-0191087988910.1007/s13238-018-0510-2SCFβ-TRCP E3 ubiquitin ligase targets the tumor suppressor ZNRF3 for ubiquitination and degradationYanpeng Ci0Xiaoning Li1Maorong Chen2Jiateng Zhong3Brian J. North4Hiroyuki Inuzuka5Xi He6Yu Li7Jianping Guo8Xiangpeng Dai9School of Life Science and Technology, Harbin Institute of TechnologyDepartment of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical SchoolThe FM Kirby Neurobiology Center, Children’s Hospital Boston, Harvard Medical SchoolDepartment of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical SchoolDepartment of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical SchoolDepartment of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical SchoolThe FM Kirby Neurobiology Center, Children’s Hospital Boston, Harvard Medical SchoolSchool of Life Science and Technology, Harbin Institute of TechnologyDepartment of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical SchoolDepartment of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical SchoolAbstract Wnt signaling has emerged as a major regulator of tissue development by governing the self-renewal and maintenance of stem cells in most tissue types. As a key upstream regulator of the Wnt pathway, the transmembrane E3 ligase ZNRF3 has recently been established to play a role in negative regulation of Wnt signaling by targeting Frizzled (FZD) receptor for ubiquitination and degradation. However, the upstream regulation of ZNRF3, in particular the turnover of ZNRF3, is still unclear. Here we report that ZNRF3 is accumulated in the presence of proteasome inhibitor treatment independent of its E3-ubiquitin ligase activity. Furthermore, the Cullin 1-specific SCF complex containing β-TRCP has been identified to directly interact with and ubiquitinate ZNRF3 thereby regulating its protein stability. Similar with the degradation of β-catenin by β-TRCP, ZNRF3 is ubiquitinated by β-TRCP in both CKI-phosphorylation- and degron-dependent manners. Thus, our findings not only identify a novel substrate for β-TRCP oncogenic regulation, but also highlight the dual regulation of Wnt signaling by β-TRCP in a context-dependent manner where β-TRCP negatively regulates Wnt signaling by targeting β-catenin, and positively regulates Wnt signaling by targeting ZNRF3.http://link.springer.com/article/10.1007/s13238-018-0510-2ZNRF3β-TRCPWntubiquitinationCKI |
| spellingShingle | Yanpeng Ci Xiaoning Li Maorong Chen Jiateng Zhong Brian J. North Hiroyuki Inuzuka Xi He Yu Li Jianping Guo Xiangpeng Dai SCFβ-TRCP E3 ubiquitin ligase targets the tumor suppressor ZNRF3 for ubiquitination and degradation Protein & Cell ZNRF3 β-TRCP Wnt ubiquitination CKI |
| title | SCFβ-TRCP E3 ubiquitin ligase targets the tumor suppressor ZNRF3 for ubiquitination and degradation |
| title_full | SCFβ-TRCP E3 ubiquitin ligase targets the tumor suppressor ZNRF3 for ubiquitination and degradation |
| title_fullStr | SCFβ-TRCP E3 ubiquitin ligase targets the tumor suppressor ZNRF3 for ubiquitination and degradation |
| title_full_unstemmed | SCFβ-TRCP E3 ubiquitin ligase targets the tumor suppressor ZNRF3 for ubiquitination and degradation |
| title_short | SCFβ-TRCP E3 ubiquitin ligase targets the tumor suppressor ZNRF3 for ubiquitination and degradation |
| title_sort | scfβ trcp e3 ubiquitin ligase targets the tumor suppressor znrf3 for ubiquitination and degradation |
| topic | ZNRF3 β-TRCP Wnt ubiquitination CKI |
| url | http://link.springer.com/article/10.1007/s13238-018-0510-2 |
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