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Vol. 17, Issue 4, 1779-1789, April 2006

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A Role for PP1 in the Cdc2/Cyclin B–mediated Positive Feedback Activation of Cdc25

Seth S. Margolis ^* , Jennifer A. Perry ^* , Douglas H. Weitzel ^*, Christopher D. Freel ^*, Minoru Yoshida  , Timothy A. Haystead ^*, and Sally Kornbluth ^*

^* Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710; Chemical Genetics Laboratory, RIKEN, Wako, Saitama 351-0198, Japan; and CREST Research Project, Japan Science and Technology Corporation, Saitama 332-0012, Japan

Submitted August 12, 2005; Revised January 27, 2006; Accepted January 31, 2006
Monitoring Editor: Richard Assoian

The Cdc25 phosphatase promotes entry into mitosis through the removal of inhibitory phosphorylations on the Cdc2 subunit of the Cdc2/CyclinB complex. During interphase, or after DNA damage, Cdc25 is suppressed by phosphorylation at Ser287 (Xenopus numbering; Ser216 of human Cdc25C) and subsequent binding of the small acidic protein, 14-3-3. As reported recently, at the time of mitotic entry, 14-3-3 protein is removed from Cdc25 and S287 is dephosphorylated by protein phosphatase 1 (PP1). After the initial activation of Cdc25 and consequent derepression of Cdc2/CyclinB, Cdc25 is further activated through a Cdc2-catalyzed positive feedback loop. Although the existence of such a loop has been appreciated for some time, the molecular mechanism for this activation has not been described. We report here that phosphorylation of S285 by Cdc2 greatly enhances recruitment of PP1 to Cdc25, thereby accelerating S287 dephosphorylation and mitotic entry. Moreover, we show that two other previously reported sites of Cdc2-catalyzed phosphorylation on Cdc25 are required for maximal biological activity of Cdc25, but they do not contribute to PP1 regulation and do not act solely through controlling S287 phosphorylation. Therefore, multiple mechanisms, including enhanced recruitment of PP1, are used to promote full activation of Cdc25 at the time of mitotic entry.

These authors contributed equally to this work.

Address correspondence to: Sally Kornbluth (kornb001{at}mc.duke.edu).

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