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MBC in Press, published online ahead of print July 11, 2003
Mol. Biol. Cell 10.1091/mbc.E03-02-0061

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Submitted on February 3, 2003
Revised on May 9, 2003
Accepted on June 6, 2003

Regulation of Cdc2/cyclin B activation in Xenopus egg extracts via inhibitory phosphorylation of Cdc25C phosphatase by Ca2+/CaM-dependent kinase II

James R.A. Hutchins, Dina Dikovskaya1, and Paul R. Clarke*

1 Division of Cell and Developmental Biology, School of Life Sciences, WTB/MSI Complex, University of Dundee, Dundee, DD1 5EH, Scotland, UK

* Corresponding author. E-mail address: paul.clarke{at}cancer.org.uk.

Activation of Cdc2/cyclin B kinase and entry into mitosis requires dephosphorylation of inhibitory sites on Cdc2 by Cdc25 phosphatase. In vertebrates, Cdc25C is inhibited by phosphorylation at a single site targeted by the checkpoint kinases Chk1 and Cds1/Chk2 in response to DNA damage or replication arrest. In Xenopus early embryos, the inhibitory site on Cdc25C (S287) is also phosphorylated by a distinct protein kinase that may determine the intrinsic timing of the cell cycle. Here, we show that S287-kinase activity is repressed in extracts of unfertilized Xenopus eggs arrested in M-phase, but is rapidly stimulated upon release into interphase by addition of Ca2+, which mimics fertilization. S287-kinase activity is not dependent on cyclin B degradation or inactivation of Cdc2/cyclin B kinase, indicating a direct mechanism of activation by Ca2+. Indeed, inhibitor studies identify the predominant S287-kinase as Ca2+/calmodulin-dependent protein kinase II (CaMKII). CaMKII phosphorylates Cdc25C efficiently on S287 in vitro and, like Chk1, is inhibited by 7-hydroxystaurosporine (UCN-01) and debromohymenialdesine (DBH), compounds which abrogate G2 arrest in somatic cells. CaMKII delays Cdc2/cyclin B activation via phosphorylation of Cdc25C at S287 in egg extracts, indicating that this pathway regulates the timing of mitosis during the early embryonic cell cycle.




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