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Journal of Cancer Prevention

Original Article

J Cancer Prev 2021; 26(3): 174-182

Published online September 30, 2021

© Korean Society of Cancer Prevention

F-box Protein βTrCP1 Is a Substrate of Extracellular Signal-regulated Kinase 2

Cheol-Jung Lee1,2,* , Ga-Eun Lee1,* , Hyun-Jung An1 , Eun Suh Cho3 , Weidong Chen1 , Joo Young Lee1 , Han Chang Kang1 , Hye Suk Lee1 , Yong-Yeon Cho1

1BRL & BK21-4th Team, College of Pharmacy, The Catholic University of Korea, Bucheon, 2Research Center for Materials Analysis, Korea Basic Science Institute, Daejeon, Korea, 3Department of Biochemistry, College of Biological Sciences, University of Minnesota, Minneapolis, MN, USA

Correspondence to :
Yong-Yeon Cho, E-mail:,
*These authors contributed equally to this study.

Received: August 24, 2021; Revised: September 10, 2021; Accepted: September 13, 2021

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.


F-box proteins, consisting of 69 members which are organized into the three subclasses FBXW, FBXL, and FBXO, are the substrate specific recognition subunits of the SKP1-Cullin 1-F-box protein E3 ligase complex. Although βTrCP 1 and 2, members of the FBXW subfamily, are known to regulate some protein stability, molecular mechanisms by which these proteins can recognize proper substrates are unknown. In this study, it was found that βTrCP1 showed strong interaction with members of mitogen-activated protein kinases. Although extracellular signal-regulated kinase (ERK) 3, p38β, and p38δ showed weak interactions, ERK2 specifically interacted with βTrCP1 as assessed by immunoprecipitation. In interaction domain determination experiments, we found that ERK2 interacted with two independent ERK docking sites located in the F-box domain and linker domain, but not the WD40 domain, of βTrCP1. Notably, mutations of βTrCP1 at the ERK docking sites abolished the interaction with ERK2. βTrCP1 underwent phosphorylation by EGF stimulation, while the presence of the mitogen-activated protein kinase kinases inhibitor U0126, genetic silencing by sh-ERK2, and mutation of the ERK docking site of βTrCP1 inhibited phosphorylation. This inhibition of βTrCP1 phosphorylation resulted in a shortened half-life and low protein levels. These results suggest that ERK2-mediated βTrCP1 phosphorylation may induce the destabilization of βTrCP1.

Keywords: Beta transducin repeat-containing protein, ERK pathway, Protein interaction domains, Binding site, Phosphorylation

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