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Nat Struct Mol Biol. 2010 Sep;17(9):1051-7. doi: 10.1038/nsmb.1868. Epub 2010 Aug 8.

An overlapping kinase and phosphatase docking site regulates activity of the retinoblastoma protein.

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1
Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, California, USA.

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.

PMID:
20694007
PMCID:
PMC2933323
DOI:
10.1038/nsmb.1868
[Indexed for MEDLINE]
Free PMC Article
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