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Molecular and Cellular Biology, July 1999, p. 5113-5123, Vol. 19, No. 7
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Overproduction of Human Myt1 Kinase Induces a G2 Cell Cycle Delay by Interfering with the Intracellular Trafficking of Cdc2-Cyclin B1 Complexes

Feng Liu,1,dagger Cynthia Rothblum-Oviatt,1 Christine E. Ryan,1,2 and Helen Piwnica-Worms1,2,*

Department of Cell Biology and Physiology1 and Howard Hughes Medical Institute,2 Washington University School of Medicine, St. Louis, Missouri 63110-1093

Received 26 January 1999/Returned for modification 8 March 1999/Accepted 5 April 1999

The Myt1 protein kinase functions to negatively regulate Cdc2-cyclin B complexes by phosphorylating Cdc2 on threonine 14 and tyrosine 15. Throughout interphase, human Myt1 localizes to the endoplasmic reticulum and Golgi complex, whereas Cdc2-cyclin B1 complexes shuttle between the nucleus and the cytoplasm. Here we report that overproduction of either kinase-active or kinase-inactive forms of Myt1 blocked the nuclear-cytoplasmic shuttling of cyclin B1 and caused cells to delay in the G2 phase of the cell cycle. The COOH-terminal 63 amino acids of Myt1 were identified as a Cdc2-cyclin B1 interaction domain. Myt1 mutants lacking this domain no longer bound cyclin B1 and did not efficiently phosphorylate Cdc2-cyclin B1 complexes in vitro. In addition, cells overproducing mutant forms of Myt1 lacking the interaction domain exhibited normal trafficking of cyclin B1 and unperturbed cell cycle progression. These results suggest that the docking of Cdc2-cyclin B1 complexes to the COOH terminus of Myt1 facilitates the phosphorylation of Cdc2 by Myt1 and that overproduction of Myt1 perturbs cell cycle progression by sequestering Cdc2-cyclin B1 complexes in the cytoplasm.

* Corresponding author. Mailing address: Department of Cell Biology and Physiology and Howard Hughes Medical Institute, Washington University School of Medicine, Box 8228, 660 South Euclid Ave., St. Louis, MO 63110. Phone: (314) 362-6812. Fax: (314) 362-3709. E-mail: hpiwnica{at}cellbio.wustl.edu.

dagger Present address: Oncology Disease Group, Hoechst Marion Roussel, Bridgewater, NJ 08807.

Molecular and Cellular Biology, July 1999, p. 5113-5123, Vol. 19, No. 7
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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