biostudies-literatureLiu PNational Natural Science Foundation of China (National Science Foundation of China)1-13https://www.ebi.ac.uk/biostudies/studies/S-EPMC8738747biostudies-literatureUnknown29(1)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^FBXO22 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. FBXO22 mediates BAG3 ubiquitination and degradation that requires ERK-dependent BACell death and differentiationGlobal identification of phospho-dependent SCF substrates reveals a FBXO22 phosphodegron and an ERK-FBXO22-BAG3 axis in tumorigenesis.PMC87387478177301832071432, 81872888, 917532037147307481821005Tan MZhang JLiu PDai WHuang MJi JLiu WLiu ZZhao LCong XJia XZhai LNi DChen YLiu BLiao SWang XPan LfalseGlobal 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, 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^FBXO22 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. FBXO22 mediates BAG3 ubiquitination and degradation that requires ERK-dependent BA2022-01-01T00:00:00Z2022 Jan2025-04-21T15:22:43.985Z2025-02-19T03:30:49.172ZS-EPMC87387473421584610.1038/s41418-021-00827-7