FBW7 targets KLF10 for ubiquitin-dependent degradation

Su Yu; Feng Wang; Xiao Tan; Guo-Li Gao; Wei-Juan Pan; Yi Luan; Xin Ge

doi:10.1016/j.bbrc.2017.11.187

FBW7 targets KLF10 for ubiquitin-dependent degradation

Biochem Biophys Res Commun. 2018 Jan 8;495(2):2092-2097. doi: 10.1016/j.bbrc.2017.11.187. Epub 2017 Dec 2.

Authors

Su Yu¹, Feng Wang², Xiao Tan³, Guo-Li Gao⁴, Wei-Juan Pan⁵, Yi Luan⁶, Xin Ge⁷

Affiliations

¹ Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai, 200241, China; Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 201306, China.
² Shanghai Tenth People's Hospital of Tongji University, Tongji University School of Medicine, Shanghai 200072, China.
³ Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, Tongji University School of Medicine, Shanghai 200072, China.
⁴ School of Life Science and Technology, Tongji University, Shanghai 200072, China.
⁵ Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Shanghai, 200241, China.
⁶ Department of Central Laboratory, Shanghai Tenth People's Hospital of Tongji University, Tongji University School of Medicine, Shanghai 200072, China. Electronic address: luanyi@tongji.edu.cn.
⁷ Department of Clinical Medicine, Shanghai Tenth People's Hospital Tongji University School of Medicine, Shanghai 200072, China. Electronic address: xin.ge@tongji.edu.cn.

PMID: 29198712
DOI: 10.1016/j.bbrc.2017.11.187

Abstract

FBW7, a key component of SCF^FBW7 E3 ubiquitin ligase, targets various proteins for degradation via the conserved Cdc4 phosphodegron (CPD) in substrates. In this study, we report that KLF10 is degraded by FBW7 via a conserved CPD. Through systematic analysis of the degradation of KLF transcription factors by FBW7, we identified KLF10 as a novel degradation target of FBW7. Ectopic expression of FBW7 markedly promoted the degradation of KLF10 while knockdown of endogenous FBW7 increased the protein levels of KLF10. In addition, simultaneous mutations of both threonine 82 (T82) and serine 86 (S86) significantly reduced the FBW7-mediated KLF10 degradation. Moreover, KLF10 containing a conserved putative CPD (TPPXSP) from amino acids 82 to 87, directly interacted with WD40 domain of FBW7 in a phosphorylation-dependent manner. Importantly, FBW7 could reverse the KLF10-mediated inhibition of Smad7 activity. Thus, our study uncovers a novel regulatory mechanism underlying which KLF10 stability and its biological function are mediated by FBW7.

Keywords: CPD; Degradation; FBW7; KLF10; Ubiquitin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites
Early Growth Response Transcription Factors / chemistry
Early Growth Response Transcription Factors / metabolism*
Enzyme Activation
F-Box-WD Repeat-Containing Protein 7 / chemistry
F-Box-WD Repeat-Containing Protein 7 / metabolism*
HEK293 Cells
HeLa Cells
Humans
Kruppel-Like Transcription Factors / chemistry
Kruppel-Like Transcription Factors / metabolism*
Protein Binding
Protein Interaction Mapping
Substrate Specificity
Ubiquitin / metabolism*
Ubiquitinated Proteins / chemistry
Ubiquitinated Proteins / metabolism*
Ubiquitination / physiology*

Substances

Early Growth Response Transcription Factors
F-Box-WD Repeat-Containing Protein 7
FBXW7 protein, human
KLF10 protein, human
Kruppel-Like Transcription Factors
Ubiquitin
Ubiquitinated Proteins