title: An overlapping kinase and phosphatase docking site regulates activity of the retinoblastoma protein.
abstract: The phosphorylation state and corresponding activity of the retinoblastoma tumor suppressor protein (Rb) are modulated by a balance of kinase and phosphatase activities. Here we characterize the association of Rb with the catalytic subunit of protein phosphatase 1 (PP1c). A crystal structure identifies an enzyme docking site in the Rb C-terminal domain that is required for efficient PP1c activity toward Rb. The phosphatase docking site overlaps with the known docking site for cyclin-dependent kinase (Cdk), and PP1 competition with Cdk-cyclins for Rb binding is sufficient to retain Rb activity and block cell-cycle advancement. These results provide the first detailed molecular insights into Rb activation and establish a novel mechanism for Rb regulation in which kinase and phosphatase compete for substrate docking.
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, California, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hirschi
authors.forename: Matthew
authors.initials: M
authors.lastname: Cecchini
authors.forename: Rachel C
authors.initials: RC
authors.lastname: Steinhardt
authors.forename: Michael R
authors.initials: MR
authors.lastname: Schamber
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Dick
authors.forename: Seth M
authors.initials: SM
authors.lastname: Rubin
mesh_terms: D002453:Cell Cycle; D002460:Cell Line; D018360:Crystallography, X-Ray; D051357:Cyclin-Dependent Kinase 2 / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D010766:Phosphorylation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D054645:Protein Phosphatase 1 / Q000737:chemistry* / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D016160:Retinoblastoma Protein; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D054645:Protein Phosphatase 1