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

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.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Binding Sites, Blotting, Western, Cell Line, Tumor, Epithelial-Mesenchymal Transition, F-Box Proteins, HEK293 Cells, HeLa Cells, Hep G2 Cells, Homeodomain Proteins, Humans, MCF-7 Cells, MicroRNAs, Microscopy, Fluorescence, Multiprotein Complexes, Nuclear Proteins, Protein Binding, RNA Interference, Repressor Proteins, S-Phase Kinase-Associated Proteins, SKP Cullin F-Box Protein Ligases, Snail Family Transcription Factors, Transcription Factors, Twist-Related Protein 1, Ubiquitin-Protein Ligases, Ubiquitination, Zinc Finger E-box Binding Homeobox 2
Oncotarget
Date: Jan. 20, 2015
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