The PP2A-B56 Phosphatase Opposes Cyclin E Autocatalytic Degradation via Site-Specific Dephosphorylation
| Autor: | Ryan J. Davis, Jherek Swanger, Bridget T. Hughes, Bruce E. Clurman |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
F-Box-WD Repeat-Containing Protein 7 Cyclin E Ubiquitin-Protein Ligases Cell Cycle Proteins F-box protein Phosphoserine 03 medical and health sciences Cyclin-dependent kinase Humans Protein Phosphatase 2 Phosphorylation Molecular Biology Cyclin biology Protein Stability Kinase F-Box Proteins Cell Cycle Cyclin-dependent kinase 2 Cell Biology Cell cycle HCT116 Cells Ubiquitin ligase Cell biology Protein Subunits 030104 developmental biology Proteolysis Biocatalysis biology.protein HeLa Cells Research Article |
| Zdroj: | Molecular and Cellular Biology. 37 |
| ISSN: | 1098-5549 |
| DOI: | 10.1128/mcb.00657-16 |
| Popis: | 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 SCFFbw7 ubiquitin 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. |
| Databáze: | OpenAIRE |
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