KMID : 1140220210260030174
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´ëÇѾϿ¹¹æÇÐȸÁö 2021 Volume.26 No. 3 p.174 ~ p.182
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F-box Protein ¥âTrCP1 Is a Substrate of Extracellular Signal-regulated Kinase 2
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Lee Cheol-Jung
Lee Ga-Eun An Hyun-Jung Cho Eun-Suh Chen Weidong Lee Joo-Young Kang Han-Chang Lee Hye-Suk Cho Yong-Yeon
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Abstract
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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 ¥âTrCP 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 ¥âTrCP1 showed strong interaction with members of mitogen-activated protein kinases. Although extracellular signal-regulated kinase (ERK) 3, p38¥â, and p38¥ä showed weak interactions, ERK2 specifically interacted with ¥âTrCP1 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 ¥âTrCP1. Notably, mutations of ¥âTrCP1 at the ERK docking sites abolished the interaction with ERK2. ¥âTrCP1 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 ¥âTrCP1 inhibited phosphorylation. This inhibition of ¥âTrCP1 phosphorylation resulted in a shortened half-life and low protein levels. These results suggest that ERK2-mediated ¥âTrCP1 phosphorylation may induce the destabilization of ¥âTrCP1.
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KEYWORD
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Beta transducin repeat-containing protein, ERK pathway, Protein interaction domains, Binding site, Phosphorylation
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