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FBXW7-mediated ERK3 degradation regulates the proliferation of lung cancer cells
Extracellular signal-regulated kinase 3 (ERK3) is an atypical member of the mitogen-activated protein kinase (MAPK) family, members of which play essential roles in diverse cellular processes during carcinogenesis, including cell proliferation, differentiation, migration, and invasion. Unlike other...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8813941/ https://www.ncbi.nlm.nih.gov/pubmed/35022544 http://dx.doi.org/10.1038/s12276-021-00721-9 |
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author | An, Hyun-Jung Lee, Cheol-Jung Lee, Ga-Eun Choi, Youngwon Jeung, Dohyun Chen, Weidong Lee, Hye Suk Kang, Han Chang Lee, Joo Young Kim, Dae Joon Choi, Jin-Sung Cho, Eun Suh Choi, Jong-Soon Cho, Yong-Yeon |
author_facet | An, Hyun-Jung Lee, Cheol-Jung Lee, Ga-Eun Choi, Youngwon Jeung, Dohyun Chen, Weidong Lee, Hye Suk Kang, Han Chang Lee, Joo Young Kim, Dae Joon Choi, Jin-Sung Cho, Eun Suh Choi, Jong-Soon Cho, Yong-Yeon |
author_sort | An, Hyun-Jung |
collection | PubMed |
description | Extracellular signal-regulated kinase 3 (ERK3) is an atypical member of the mitogen-activated protein kinase (MAPK) family, members of which play essential roles in diverse cellular processes during carcinogenesis, including cell proliferation, differentiation, migration, and invasion. Unlike other MAPKs, ERK3 is an unstable protein with a short half-life. Although deubiquitination of ERK3 has been suggested to regulate the activity, its ubiquitination has not been described in the literature. Here, we report that FBXW7 (F-box and WD repeat domain-containing 7) acts as a ubiquitination E3 ligase for ERK3. Mammalian two-hybrid assay and immunoprecipitation results demonstrated that ERK3 is a novel binding partner of FBXW7. Furthermore, complex formation between ERK3 and the S-phase kinase-associated protein 1 (SKP1)-cullin 1-F-box protein (SCF) E3 ligase resulted in the destabilization of ERK3 via a ubiquitination-mediated proteasomal degradation pathway, and FBXW7 depletion restored ERK3 protein levels by inhibiting this ubiquitination. The interaction between ERK3 and FBXW7 was driven by binding between the C34D of ERK3, especially at Thr417 and Thr421, and the WD40 domain of FBXW7. A double mutant of ERK3 (Thr417 and Thr421 to alanine) abrogated FBXW7-mediated ubiquitination. Importantly, ERK3 knockdown inhibited the proliferation of lung cancer cells by regulating the G(1)/S-phase transition of the cell cycle. These results show that FBXW7-mediated ERK3 destabilization suppresses lung cancer cell proliferation in vitro. |
format | Online Article Text |
id | pubmed-8813941 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-88139412022-02-09 FBXW7-mediated ERK3 degradation regulates the proliferation of lung cancer cells An, Hyun-Jung Lee, Cheol-Jung Lee, Ga-Eun Choi, Youngwon Jeung, Dohyun Chen, Weidong Lee, Hye Suk Kang, Han Chang Lee, Joo Young Kim, Dae Joon Choi, Jin-Sung Cho, Eun Suh Choi, Jong-Soon Cho, Yong-Yeon Exp Mol Med Article Extracellular signal-regulated kinase 3 (ERK3) is an atypical member of the mitogen-activated protein kinase (MAPK) family, members of which play essential roles in diverse cellular processes during carcinogenesis, including cell proliferation, differentiation, migration, and invasion. Unlike other MAPKs, ERK3 is an unstable protein with a short half-life. Although deubiquitination of ERK3 has been suggested to regulate the activity, its ubiquitination has not been described in the literature. Here, we report that FBXW7 (F-box and WD repeat domain-containing 7) acts as a ubiquitination E3 ligase for ERK3. Mammalian two-hybrid assay and immunoprecipitation results demonstrated that ERK3 is a novel binding partner of FBXW7. Furthermore, complex formation between ERK3 and the S-phase kinase-associated protein 1 (SKP1)-cullin 1-F-box protein (SCF) E3 ligase resulted in the destabilization of ERK3 via a ubiquitination-mediated proteasomal degradation pathway, and FBXW7 depletion restored ERK3 protein levels by inhibiting this ubiquitination. The interaction between ERK3 and FBXW7 was driven by binding between the C34D of ERK3, especially at Thr417 and Thr421, and the WD40 domain of FBXW7. A double mutant of ERK3 (Thr417 and Thr421 to alanine) abrogated FBXW7-mediated ubiquitination. Importantly, ERK3 knockdown inhibited the proliferation of lung cancer cells by regulating the G(1)/S-phase transition of the cell cycle. These results show that FBXW7-mediated ERK3 destabilization suppresses lung cancer cell proliferation in vitro. Nature Publishing Group UK 2022-01-12 /pmc/articles/PMC8813941/ /pubmed/35022544 http://dx.doi.org/10.1038/s12276-021-00721-9 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article An, Hyun-Jung Lee, Cheol-Jung Lee, Ga-Eun Choi, Youngwon Jeung, Dohyun Chen, Weidong Lee, Hye Suk Kang, Han Chang Lee, Joo Young Kim, Dae Joon Choi, Jin-Sung Cho, Eun Suh Choi, Jong-Soon Cho, Yong-Yeon FBXW7-mediated ERK3 degradation regulates the proliferation of lung cancer cells |
title | FBXW7-mediated ERK3 degradation regulates the proliferation of lung cancer cells |
title_full | FBXW7-mediated ERK3 degradation regulates the proliferation of lung cancer cells |
title_fullStr | FBXW7-mediated ERK3 degradation regulates the proliferation of lung cancer cells |
title_full_unstemmed | FBXW7-mediated ERK3 degradation regulates the proliferation of lung cancer cells |
title_short | FBXW7-mediated ERK3 degradation regulates the proliferation of lung cancer cells |
title_sort | fbxw7-mediated erk3 degradation regulates the proliferation of lung cancer cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8813941/ https://www.ncbi.nlm.nih.gov/pubmed/35022544 http://dx.doi.org/10.1038/s12276-021-00721-9 |
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