Lee CJ, Lee GE, An HJ, Cho ES, Chen W, Lee JY, Kang HC, Lee HS, Cho YY

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 ?TrCP 1 and 2, members of the FBXW subfamily, are known to regulate some protein stability, molecular mechanisms ...

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by which these proteins can recognize proper substrates are unknown. In this study, it was found that ?TrCP1 showed strong interaction with members of mitogen-activated protein kinases. Although extracellular signal-regulated kinase (ERK) 3, p38?, and p38? showed weak interactions, ERK2 specifically interacted with ?TrCP1 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 ?TrCP1. Notably, mutations of ?TrCP1 at the ERK docking sites abolished the interaction with ERK2. ?TrCP1 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 ?TrCP1 inhibited phosphorylation. This inhibition of ?TrCP1 phosphorylation resulted in a shortened half-life and low protein levels. These results suggest that ERK2-mediated ?TrCP1 phosphorylation may induce the destabilization of ?TrCP1.

Date: Sep. 30, 2021

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