An Overlapping Kinase and Phosphatase Docking Site Regulates Activity of the Retinoblastoma Protein

Authors

Alexander Hirschi, University of California - Santa Cruz
Matthew Cecchini, The University of Western Ontario
Rachel C. Steinhardt, University of California - Santa Cruz
Michael R. Schamber, University of California - Santa Cruz
Frederick A. Dick, The University of Western Ontario
Seth M. Rubin, University of California - Santa Cruz

Document Type

Article

Publication Date

9-2010

Journal

Nature Structural & Molecular Biology

Volume

17

Issue

9

First Page

1051

Last Page

1057

URL with Digital Object Identifier

http://dx.doi.org/10.1038/nsmb.1868

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.

Notes

PMCID: PMC2933323 [Available on 2011/3/1]