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Vol. 20, Issue 22, 4777-4789, November 15, 2009

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The M Phase Kinase Greatwall (Gwl) Promotes Inactivation of PP2A/B55, a Phosphatase Directed Against CDK Phosphosites

Priscila V. Castilho^*,, Byron C. Williams^*,, Satoru Mochida, Yong Zhao^*, and Michael L. Goldberg^*

*Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853; and Cancer Research UK, Clare Hall Laboratories, South Mimms, Herts EN6 3LD, United Kingdom

Submitted July 31, 2009; Revised September 14, 2009; Accepted September 22, 2009
Monitoring Editor: Orna Cohen-Fix

We have previously shown that Greatwall kinase (Gwl) is required for M phase entry and maintenance in Xenopus egg extracts. Here, we demonstrate that Gwl plays a crucial role in a novel biochemical pathway that inactivates, specifically during M phase, "antimitotic" phosphatases directed against phosphorylations catalyzed by cyclin-dependent kinases (CDKs). A major component of this phosphatase activity is heterotrimeric PP2A containing the B55 regulatory subunit. Gwl is activated during M phase by Cdk1/cyclin B (MPF), but once activated, Gwl promotes PP2A/B55 inhibition with no further requirement for MPF. In the absence of Gwl, PP2A/B55 remains active even when MPF levels are high. The removal of PP2A/B55 corrects the inability of Gwl-depleted extracts to enter M phase. These findings support the hypothesis that M phase requires not only high levels of MPF function, but also the suppression, through a Gwl-dependent mechanism, of phosphatase(s) that would otherwise remove MPF-driven phosphorylations.

These authors contributed equally to this work.

Address correspondence to: Michael L. Goldberg (mlg11{at}cornell.edu)

Abbreviations used: CDK, cyclin-dependent kinase; CSF, cytostatic factor; Gwl, Greatwall kinase; MPF, M phase–promoting factor (Cdk1/cyclin B); OA, okadaic acid.

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