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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.

SUBMITTER: Hirschi A

PROVIDER: S-EPMC2933323 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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

Hirschi Alexander A Cecchini Matthew M Steinhardt Rachel C RC Schamber Michael R MR Dick Frederick A FA Rubin Seth M SM

Nature structural & molecular biology 20100808 9

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 ki ...[more]

PMID: 20694007

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