Lysine Demethylase KDM2A Promotes Proteasomal Degradation of TCF/LEF Transcription Factors in a Neddylation-Dependent Manner
Canonical Wnt signaling is essential for a plethora of biological processes ranging from early embryogenesis to aging. Malfunctions of this crucial signaling pathway are associated with various developmental defects and diseases, including cancer. Although TCF/LEF transcription factors (TCF/LEFs) ar...
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| Format: | Article |
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MDPI AG
2023-11-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/12/22/2620 |
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| author | Tijana Šopin František Liška Tomáš Kučera Dušan Cmarko Tomáš Vacík |
| author_facet | Tijana Šopin František Liška Tomáš Kučera Dušan Cmarko Tomáš Vacík |
| author_sort | Tijana Šopin |
| collection | DOAJ |
| description | Canonical Wnt signaling is essential for a plethora of biological processes ranging from early embryogenesis to aging. Malfunctions of this crucial signaling pathway are associated with various developmental defects and diseases, including cancer. Although TCF/LEF transcription factors (TCF/LEFs) are known to be essential for this pathway, the regulation of their intracellular levels is not completely understood. Here, we show that the lysine demethylase KDM2A promotes the proteasomal destabilization of TCF/LEFs independently of its demethylase domain. We found that the KDM2A-mediated destabilization of TCF/LEFs is dependent on the KDM2A zinc finger CXXC domain. Furthermore, we identified the C-terminal region of TCF7L2 and the CXXC domain of KDM2A as the domains responsible for the interaction between the two proteins. Our study is also the first to show that endogenous TCF/LEF proteins undergo KDM2A-mediated proteasomal degradation in a neddylation-dependent manner. Here, we reveal a completely new mechanism that affects canonical Wnt signaling by regulating the levels of TCF/LEF transcription factors through their KDM2A-promoted proteasomal degradation. |
| first_indexed | 2024-03-09T16:55:29Z |
| format | Article |
| id | doaj.art-29d0f73a134c45ca9f0c952a0ddea99a |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T16:55:29Z |
| publishDate | 2023-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-29d0f73a134c45ca9f0c952a0ddea99a2023-11-24T14:35:19ZengMDPI AGCells2073-44092023-11-011222262010.3390/cells12222620Lysine Demethylase KDM2A Promotes Proteasomal Degradation of TCF/LEF Transcription Factors in a Neddylation-Dependent MannerTijana Šopin0František Liška1Tomáš Kučera2Dušan Cmarko3Tomáš Vacík4Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital in Prague, 128 01 Prague, Czech RepublicInstitute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital in Prague, 128 01 Prague, Czech RepublicInstitute of Histology and Embryology, First Faculty of Medicine, Charles University and General University Hospital in Prague, 128 01 Prague, Czech RepublicInstitute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital in Prague, 128 01 Prague, Czech RepublicInstitute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital in Prague, 128 01 Prague, Czech RepublicCanonical Wnt signaling is essential for a plethora of biological processes ranging from early embryogenesis to aging. Malfunctions of this crucial signaling pathway are associated with various developmental defects and diseases, including cancer. Although TCF/LEF transcription factors (TCF/LEFs) are known to be essential for this pathway, the regulation of their intracellular levels is not completely understood. Here, we show that the lysine demethylase KDM2A promotes the proteasomal destabilization of TCF/LEFs independently of its demethylase domain. We found that the KDM2A-mediated destabilization of TCF/LEFs is dependent on the KDM2A zinc finger CXXC domain. Furthermore, we identified the C-terminal region of TCF7L2 and the CXXC domain of KDM2A as the domains responsible for the interaction between the two proteins. Our study is also the first to show that endogenous TCF/LEF proteins undergo KDM2A-mediated proteasomal degradation in a neddylation-dependent manner. Here, we reveal a completely new mechanism that affects canonical Wnt signaling by regulating the levels of TCF/LEF transcription factors through their KDM2A-promoted proteasomal degradation.https://www.mdpi.com/2073-4409/12/22/2620KDM2Acanonical Wnt signalingTCF/LEFubiquitinationneddylation |
| spellingShingle | Tijana Šopin František Liška Tomáš Kučera Dušan Cmarko Tomáš Vacík Lysine Demethylase KDM2A Promotes Proteasomal Degradation of TCF/LEF Transcription Factors in a Neddylation-Dependent Manner Cells KDM2A canonical Wnt signaling TCF/LEF ubiquitination neddylation |
| title | Lysine Demethylase KDM2A Promotes Proteasomal Degradation of TCF/LEF Transcription Factors in a Neddylation-Dependent Manner |
| title_full | Lysine Demethylase KDM2A Promotes Proteasomal Degradation of TCF/LEF Transcription Factors in a Neddylation-Dependent Manner |
| title_fullStr | Lysine Demethylase KDM2A Promotes Proteasomal Degradation of TCF/LEF Transcription Factors in a Neddylation-Dependent Manner |
| title_full_unstemmed | Lysine Demethylase KDM2A Promotes Proteasomal Degradation of TCF/LEF Transcription Factors in a Neddylation-Dependent Manner |
| title_short | Lysine Demethylase KDM2A Promotes Proteasomal Degradation of TCF/LEF Transcription Factors in a Neddylation-Dependent Manner |
| title_sort | lysine demethylase kdm2a promotes proteasomal degradation of tcf lef transcription factors in a neddylation dependent manner |
| topic | KDM2A canonical Wnt signaling TCF/LEF ubiquitination neddylation |
| url | https://www.mdpi.com/2073-4409/12/22/2620 |
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