title: Skp1-Cul1-F-box ubiquitin ligase (SCF(βTrCP))-mediated destruction of the ubiquitin-specific protease USP37 during G2-phase promotes mitotic entry.
abstract: Ubiquitin-mediated proteolysis is a key regulatory process in cell cycle progression. The Skp1-Cul1-F-box (SCF) and anaphase-promoting complex (APC) ubiquitin ligases target numerous components of the cell cycle machinery for destruction. Throughout the cell cycle, these ligases cooperate to maintain precise levels of key regulatory proteins, and indirectly, each other. Recently, we have identified the deubiquitinase USP37 as a regulator of the cell cycle. USP37 expression is cell cycle-regulated, being expressed in late G(1) and ubiquitinated by APC(Cdh1) in early G(1). Here we report that in addition to destruction at G(1), a major fraction of USP37 is degraded at the G(2)/M transition, prior to APC substrates and similar to SCF(βTrCP) substrates. Consistent with this hypothesis, USP37 interacts with components of the SCF in a βTrCP-dependent manner. Interaction with βTrCP and subsequent degradation is phosphorylation-dependent and is mediated by the Polo-like kinase (Plk1). USP37 is stabilized in G(2) by depletion of βTrCP as well as chemical or genetic manipulation of Plk1. Similarly, mutation of the phospho-sites abolishes βTrCP binding and renders USP37 resistant to Plk1 activity. Expression of this mutant hinders the G(2)/M transition. Our data demonstrate that tight regulation of USP37 levels is required for proper cell cycle progression.
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
authors.forename: Amy C
authors.initials: AC
authors.lastname: Burrows
authors.forename: John
authors.initials: J
authors.lastname: Prokop
authors.forename: Matthew K
authors.initials: MK
authors.lastname: Summers
mesh_terms: D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism; D044842:Cullin Proteins / Q000378:metabolism*; D010450:Endopeptidases / Q000737:chemistry*; D016195:G2 Phase; D015971:Gene Expression Regulation, Enzymologic; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008938:Mitosis; D009154:Mutation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism*; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism*; D025801:Ubiquitin / Q000737:chemistry; D000097869:Polo-Like Kinase 1
chemical_list: D018797:Cell Cycle Proteins; D044842:Cullin Proteins; D010450:Endopeptidases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D044786:S-Phase Kinase-Associated Proteins; D044843:SKP Cullin F-Box Protein Ligases; D025801:Ubiquitin; D000097869:Polo-Like Kinase 1; C100318:Cullin 1; C097351:SKP1 protein, human; C559980:USP37 protein, human