Global identification of phospho-dependent SCF substrates reveals a FBXO22 phosphodegron and an ERK-FBXO22-BAG3 axis in tumorigenesis

SKP1-CUL1-F-box (SCF) ubiquitin ligases play fundamental roles in cellular functions. Typically, substrate phosphorylation is required for SCF recognition and subsequent degradation. However, phospho-dependent substrates remain largely unidentified. Here, using quantitative phoshoproteome approach,...

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Published in:	Cell death and differentiation 2022-01, Vol.29 (1), p.1-13
Main Authors:	Liu, Ping, Cong, Xiaoji, Liao, Shengjie, Jia, Xinglong, Wang, Xiaomin, Dai, Wei, Zhai, Linhui, Zhao, Lei, Ji, Jing, Ni, Duan, Liu, Zhiwei, Chen, Yulu, Pan, Lulu, Liu, Wei, Zhang, Jian, Huang, Min, Liu, Bin, Tan, Minjia
Format:	Article
Language:	eng
Subjects:	Adaptor Proteins, Signal Transducing - metabolism Apoptosis Apoptosis Regulatory Proteins - metabolism Carcinogenesis Cell cycle Cell Transformation, Neoplastic Extracellular signal-regulated kinase F-Box Proteins - genetics F-Box Proteins - metabolism Hsp70 protein Humans Phosphorylation Receptors, Cytoplasmic and Nuclear - metabolism Tumorigenesis Ubiquitin Ubiquitin - metabolism Ubiquitination
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Summary:	SKP1-CUL1-F-box (SCF) ubiquitin ligases play fundamental roles in cellular functions. Typically, substrate phosphorylation is required for SCF recognition and subsequent degradation. However, phospho-dependent substrates remain largely unidentified. Here, using quantitative phoshoproteome approach, we performed a system-wide investigation of phospho-dependent SCF substrates. This strategy identified diverse phospho-dependent candidates. Biochemical verification revealed a mechanism by which SCF recognizes the motif XXPpSPXPXX as a conserved phosphodegron to target substrates for destruction. We further demonstrated BAG3, a HSP70 co-chaperone, is a bona fide substrate of SCF . FBXO22 mediates BAG3 ubiquitination and degradation that requires ERK-dependent BAG3 phosphorylation at S377. FBXO22 depletion or expression of a stable BAG3 S377A mutant promotes tumor growth via defects in apoptosis and cell cycle progression in vitro and in vivo. In conclusion, our study identified broad phosphorylation-dependent SCF substrates and demonstrated a phosphodegron recognized by FBXO22 and a novel ERK-FBXO22-BAG3 axis involved in tumorigenesis.
ISSN:	1350-9047 1476-5403