title: The PP2A-B56 Phosphatase Opposes Cyclin E Autocatalytic Degradation via Site-Specific Dephosphorylation.
abstract: Cyclin E, in conjunction with its catalytic partner cyclin-dependent kinase 2 (CDK2), regulates cell cycle progression as cells exit quiescence and enter S-phase. Multiple mechanisms control cyclin E periodicity during the cell cycle, including phosphorylation-dependent cyclin E ubiquitylation by the SCFFbw7ubiquitin ligase. Serine 384 (S384) is the critical cyclin E phosphorylation site that stimulates Fbw7 binding and cyclin E ubiquitylation and degradation. Because S384 is autophosphorylated by bound CDK2, this presents a paradox as to how cyclin E can evade autocatalytically induced degradation in order to phosphorylate its other substrates. We found that S384 phosphorylation is dynamically regulated in cells and that cyclin E is specifically dephosphorylated at S384 by the PP2A-B56 phosphatase, thereby uncoupling cyclin E degradation from cyclin E-CDK2 activity. Furthermore, the rate of S384 dephosphorylation is high in interphase but low in mitosis. This provides a mechanism whereby interphase cells can oppose autocatalytic cyclin E degradation and maintain cyclin E-CDK2 activity while also enabling cyclin E destruction in mitosis, when inappropriate cyclin E expression is genotoxic.
authors.affiliation: Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.|Molecular and Cellular Biology Program, University of Washington, Seattle, Washington, USA.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Davis
authors.affiliation: Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Jherek
authors.initials: J
authors.lastname: Swanger
authors.affiliation: Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Bridget T
authors.initials: BT
authors.lastname: Hughes
authors.affiliation: Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA bclurman@fredhutch.org.
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Clurman
mesh_terms: D055162:Biocatalysis; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000172:deficiency / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism*; D044783:F-Box Proteins / Q000378:metabolism; D000073979:F-Box-WD Repeat-Containing Protein 7; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D055550:Protein Stability; D021122:Protein Subunits / Q000378:metabolism; D059748:Proteolysis; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D019927:Cyclin E; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C525690:PPP2R5A protein, human; D021122:Protein Subunits; D010768:Phosphoserine; D044767:Ubiquitin-Protein Ligases; D054648:Protein Phosphatase 2
keywords: cell cycle; cyclin-dependent kinases; cyclins; serine/threonine phosphatases; ubiquitination