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F-box proteins, consisting of 69 members which are organized into the three subclasses FBXW, FBXL, and FBXO, are the sub strate 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-acti vated 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 un derwent 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 phos phorylation may induce the destabilization of βTrCP1
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참고문헌 (29)
참고문헌 신청
Hubbard SR / 2007 / Receptor tyrosine kinases : mechanisms of activation and signaling / Curr Opin Cell Biol 19:117~123
Cullen PJ / 2002 / Integration of calcium and Ras signalling / Nat Rev Mol Cell Biol 3:339~348
Arul N / 2013 / A rising cancer prevention target of RSK2 in human skin cancer / Front Oncol 3:201
Kim MO / 2012 / ERK1 and ERK2 regulate embryonic stem cell self-renewal through phosphorylation of Klf4 / Nat Struct Mol Biol 19:283~290
Yoon S / 2006 / The extracellular signal-regulated kinase : multiple substrates regulate diverse cellular functions / Growth Factors 24:21~44
Cullen PJ / 2002 / Integration of calcium and Ras signalling / Nat Rev Mol Cell Biol 3:339~348
Arul N / 2013 / A rising cancer prevention target of RSK2 in human skin cancer / Front Oncol 3:201
Kim MO / 2012 / ERK1 and ERK2 regulate embryonic stem cell self-renewal through phosphorylation of Klf4 / Nat Struct Mol Biol 19:283~290
Yoon S / 2006 / The extracellular signal-regulated kinase : multiple substrates regulate diverse cellular functions / Growth Factors 24:21~44
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