The β-TrCP-FBXW2-SKP2 axis regulates lung cancer cell growth with FBXW2 acting as a tumour suppressor

Jie Xu, Weihua Zhou, Fei Yang, Guoan Chen, Haomin Li, Yongchao Zhao, Pengyuan Liu, Hua Li, Mingjia Tan, Xiufang Xiong and Yi Sun ()
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Jie Xu: University of Michigan
Weihua Zhou: University of Michigan
Fei Yang: Institute of Translational Medicine, Zhejiang University School of Medicine
Guoan Chen: University of Michigan
Haomin Li: Institute of Translational Medicine, Zhejiang University School of Medicine
Yongchao Zhao: University of Michigan
Pengyuan Liu: Institute of Translational Medicine, Zhejiang University School of Medicine
Hua Li: University of Michigan
Mingjia Tan: University of Michigan
Xiufang Xiong: Institute of Translational Medicine, Zhejiang University School of Medicine
Yi Sun: University of Michigan

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: Abstract β-TrCP and SKP2 are two well-studied F-box proteins, which often act as oncogenes. Whether and how they communicate with each other is unknown. Here we report that FBXW2, a poorly characterized F-box, is a substrate of β-TrCP1 and an E3 ligase for SKP2. While β-TrCP1 promotes FBXW2 ubiquitylation and shortens its half-life, FBXW2 does the same to SKP2. FBXW2 has tumour suppressor activity against lung cancer cells and blocks oncogenic function of both β-TrCP1 and SKP2. The levels of β-TrCP1-FBXW2-SKP2 are inversely correlated during cell cycle with FBXW2 and β-TrCP/SKP2 being high or low, respectively, in arrested cells, whereas the opposite is true in proliferating cells. Consistently, FBXW2 predicts a better patient survival, whereas β-TrCP1 and SKP2 predict a worse survival. Finally, the gain- and loss-of-function mutations of FBXW2 are found in various human cancers. Collectively, our data show that the β-TrCP-FBXW2-SKP2 axis forms an oncogene-tumour suppressor-oncogene cascade to control cancer cell growth with FBXW2 acting as a tumour suppressor by promoting SKP2 degradation.

Date: 2017
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DOI: 10.1038/ncomms14002

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