biostudies-literatureYang H牛 津 大 学 | John Fell Fund, University of OxfordCAMS | Chinese Academy of Medical Sciences Initiative for Innovative MedicineCancer Research UKUKRI | Engineering and Physical Sciences Research Council (EPSRC)CAMS | Chinese Academy of Medical Sciences Initiative for Innovative Medicine ( )UKRI | Engineering and Physical Sciences Research CouncilMedical Research Council| John Fell Fund, University of Oxford (John Fell OUP Research Fund)Wellcome TrustUKRI | Medical Research Council1332-1361https://www.ebi.ac.uk/biostudies/studies/S-EPMC12909836biostudies-literatureUnknown45(4)F-box proteins are the substrate recognition modules of the SCF (SKP1-Cullin-F-box) E3 ubiquitin ligase complex. FBXO42, an understudied member of this family, has recently emerged as a modulator of key cellular processes, including cell cycle progression, the DNA damage response, and glioma stem cell survival. In this study, we define the function of FBXO42 as a major regulator of the protein phosphatase PP4. Phosphoprotein phosphatases (PPPs) have a broad array of substrates, hence necessitating tight regulation. We observe that FBXO42 ubiquitinates the PP4 complex to govern the assembly of regulatory and catalytic subunits, with the net effect of restraining the latter's phosphatase activity. FBXO42 depletion unleashes PP4 activity, with broad cellular effects, highlighting FBXO42 as a The EMBO journalPervasive phenotypic effects of FBXO42 are promoted by regulation of PP4 phosphatase.PMC12909836RRCOER-Jun24/100003MR/X006980/1EP/N034295/12018-I2M-2-002DRCNPG May21\100002133/075097813/Z/11/ZYang HFischer RRowland JVendrell IMa YKessler BMSmith PGrieco DLoftus AEPGopala Krishna VSalerno BSouthworth ED'Angiolella VfalsePervasive phenotypic effects of FBXO42 are promoted by regulation of PP4 phosphatase.F-box proteins are the substrate recognition modules of the SCF (SKP1-Cullin-F-box) E3 ubiquitin ligase complex. FBXO42, an understudied member of this family, has recently emerged as a modulator of key cellular processes, including cell cycle progression, the DNA damage response, and glioma stem cell survival. In this study, we define the function of FBXO42 as a major regulator of the protein phosphatase PP4. Phosphoprotein phosphatases (PPPs) have a broad array of substrates, hence necessitating tight regulation. We observe that FBXO42 ubiquitinates the PP4 complex to govern the assembly of regulatory and catalytic subunits, with the net effect of restraining the latter's phosphatase activity. FBXO42 depletion unleashes PP4 activity, with broad cellular effects, highlighting FBXO42 as a 2026-01-01T00:00:00Z2026 Feb2026-07-16T04:59:29.614Z2026-07-09T13:10:11.218ZS-EPMC129098364148436410.1038/s44318-025-00675-y