Atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 controls the core epithelial-to-mesenchymal transition-inducing transcription factors

Ming Xu; Changhong Zhu; Xian Zhao; Cheng Chen; Hailong Zhang; Haihua Yuan; Rong Deng; Jinzhuo Dou; Yanli Wang; Jian Huang; Qin Chen; Bin Jiang; Jianxiu Yu

doi:10.18632/oncotarget.2825

Atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 controls the core epithelial-to-mesenchymal transition-inducing transcription factors

Oncotarget. 2015 Jan 20;6(2):979-94. doi: 10.18632/oncotarget.2825.

Authors

Ming Xu^{1

2}, Changhong Zhu², Xian Zhao², Cheng Chen², Hailong Zhang², Haihua Yuan¹, Rong Deng², Jinzhuo Dou², Yanli Wang², Jian Huang², Qin Chen², Bin Jiang¹, Jianxiu Yu³

Affiliations

¹ Institute of Oncology & Department of Oncology, Shanghai 9th People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Department of Biochemistry and Molecular Cell Biology & Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, China.State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

Abstract

Epithelial-mesenchymal transition (EMT) plays a critical role in the development of tumor metastases by enhancing migration/invasion. One of the hallmarks of EMT is loss of E-cadherin and gain of N-cadherin expression, which are regulated by the core EMT-inducing transcription factors (EMT-TFs), such as Zeb1/2, Snai1/2 and Twist1. Here, we find that EMT-TFs can be dynamically degraded by an atypical ubiquitin E3 ligase complex Skp1-Pam-Fbxo45 (SPFFbxo45) through the ubiquitin proteasome system (UPS). The key step is recognition of EMT-TFs by Fbxo45 through its SPRY domain for Zeb2, or F-box domain for the other three EMT-TFs Snai1, Snai2 and Twist1, respectively. The K48-linkaged ubiquitination capability on Zeb2 relies on its functional SBD domain. In addition, miR-27a* can directly down-regulate the expression of Fbxo45, preventing degradation of EMT-TFs and thus ensuring EMT phenotype. We suggest that Fbxo45 is a key node of the miR-27a*/Fbxo45/EMT-TFs signaling axis.

Publication types

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

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism*
Binding Sites / genetics
Blotting, Western
Cell Line, Tumor
Epithelial-Mesenchymal Transition*
F-Box Proteins / genetics
F-Box Proteins / metabolism*
HEK293 Cells
HeLa Cells
Hep G2 Cells
Homeodomain Proteins / genetics
Homeodomain Proteins / metabolism
Humans
MCF-7 Cells
MicroRNAs / genetics
Microscopy, Fluorescence
Multiprotein Complexes / metabolism
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Protein Binding
RNA Interference
Repressor Proteins / genetics
Repressor Proteins / metabolism
S-Phase Kinase-Associated Proteins / genetics
S-Phase Kinase-Associated Proteins / metabolism*
SKP Cullin F-Box Protein Ligases / genetics
SKP Cullin F-Box Protein Ligases / metabolism
Snail Family Transcription Factors
Transcription Factors / genetics
Transcription Factors / metabolism*
Twist-Related Protein 1 / genetics
Twist-Related Protein 1 / metabolism
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism*
Ubiquitination
Zinc Finger E-box Binding Homeobox 2

Substances

Adaptor Proteins, Signal Transducing
F-Box Proteins
FBXO45 protein, human
Homeodomain Proteins
MIRN27 microRNA, human
MicroRNAs
Multiprotein Complexes
Nuclear Proteins
Repressor Proteins
S-Phase Kinase-Associated Proteins
SNAI1 protein, human
SNAI2 protein, human
Snail Family Transcription Factors
TWIST1 protein, human
Transcription Factors
Twist-Related Protein 1
ZEB2 protein, human
Zinc Finger E-box Binding Homeobox 2
MYCBP2 protein, human
SKP Cullin F-Box Protein Ligases
Ubiquitin-Protein Ligases