title: Activation domain-dependent degradation of somatic Wee1 kinase.
abstract: Cell cycle progression is dependent upon coordinate regulation of kinase and proteolytic pathways. Inhibitors of cell cycle transitions are degraded to allow progression into the subsequent cell cycle phase. For example, the tyrosine kinase and Cdk1 inhibitor Wee1 is degraded during G(2) and mitosis to allow mitotic progression. Previous studies suggested that the N terminus of Wee1 directs Wee1 destruction. Using a chemical mutagenesis strategy, we report that multiple regions of Wee1 control its destruction. Most notably, we find that the activation domain of the Wee1 kinase is also required for its degradation. Mutations in this domain inhibit Wee1 degradation in somatic cell extracts and in cells without affecting the overall Wee1 structure or kinase activity. More broadly, these findings suggest that kinase activation domains may be previously unappreciated sites of recognition by the ubiquitin proteasome pathway.
authors.affiliation: Department of Cancer Biology, Scripps Research Institute, Scripps Florida, Jupiter, Florida 33458, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Owens
authors.forename: Scott
authors.initials: S
authors.lastname: Simanski
authors.forename: Christopher
authors.initials: C
authors.lastname: Squire
authors.forename: Anthony
authors.initials: A
authors.lastname: Smith
authors.forename: Jeff
authors.initials: J
authors.lastname: Cartzendafner
authors.forename: Valerie
authors.initials: V
authors.lastname: Cavett
authors.forename: Jennifer
authors.initials: J
authors.lastname: Caldwell Busby
authors.forename: Trey
authors.initials: T
authors.lastname: Sato
authors.forename: Nagi G
authors.initials: NG
authors.lastname: Ayad
mesh_terms: D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D025801:Ubiquitin
chemical_list: D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D025801:Ubiquitin; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; D046988:Proteasome Endopeptidase Complex