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KMID : 0620920220540010035
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Experimental & Molecular Medicine
2022 Volume.54 No. 1 p.35 ~ p.46
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FBXW7-mediated ERK3 degradation regulates the proliferation of lung cancer cells
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An Hyun-Jung
Lee Cheol-Jung
Lee Ga-Eun
Choi Young-Won
Jeung Do-Hyun
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
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Abstract
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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 G1/S-phase transition of the cell cycle. These results show that FBXW7-mediated ERK3 destabilization suppresses lung cancer cell proliferation in vitro.
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KEYWORD
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Protein quality control, Ubiquitylation
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