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J Biol Chem, Vol. 274, Issue 12, 7958-7968, March 19, 1999

Calcium/Calmodulin-dependent Phosphorylation and Activation of Human Cdc25-C at the G₂/M Phase Transition in HeLa Cells

Rajnikant Patel, Mark Holt, Rada Philipova^§, Stephen Moss^¶, Howard Schulman, Hiroyoshi Hidaka^**, and Michael Whitaker^§

From the Department of Biochemistry, University of Leicester, University Road, Leicester, United Kingdom LE1 7RH, the ^§ Department of Physiological Sciences. Medical School, Framlington Place, Newcastle-upon-Tyne, United Kingdom NE2 4HH, the ^¶ Medical Research Council Laboratory of Molecular Cell Biology and the Department of Pharmacology, University College London, Gower Street, London, United Kingdom WC1E 6BT, the  Department of Neurobiology, Stanford University School of Medicine, Stanford, California 94305-5401, and the ^** Department of Pharmacology, Nagoya University School of Medicine, Tsurumai-cho 65, Showa-Ku, Nagoya 466, Japan

The human tyrosine phosphatase (p54^cdc25-c) is activated by phosphorylation at mitosis entry. The phosphorylated p54^cdc25-c in turn activates the p34-cyclin B protein kinase and triggers mitosis. Although the active p34-cyclin B protein kinase can itself phosphorylate and activate p54^cdc25-c, we have investigated the possibility that other kinases may initially trigger the phosphorylation and activation of p54^cdc25-c. We have examined the effects of the calcium/calmodulin-dependent protein kinase (CaM kinase II) on p54^cdc25-c. Our in vitro experiments show that CaM kinase II can phosphorylate p54^cdc25-c and increase its phosphatase activity by 2.5-3-fold. Treatment of a synchronous population of HeLa cells with KN-93 (a water-soluble inhibitor of CaM kinase II) or the microinjection of AC3-I (a specific peptide inhibitor of CaM kinase II) results in a cell cycle block in G₂ phase. In the KN-93-arrested cells, p54^cdc25-c is not phosphorylated, p34^cdc2 remains tyrosine phosphorylated, and there is no increase in histone H1 kinase activity. Our data suggest that a calcium-calmodulin-dependent step may be involved in the initial activation of p54^cdc25-c.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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