Human wee1 maintains mitotic timing by protecting the nucleus from cytoplasmically activated Cdc2 kinase.
The wee1 tyrosine kinase and cdc25 tyrosine phosphatase of fission yeast play antagonistic roles in the induction of mitosis through cdc2 regulation. We show here that the human wee1-like tyrosine kinase is a nuclear protein that ensures the completion of DNA replication prior to mitosis in cells expressing otherwise catastrophic levels of cdc2 activators. Paradoxically, wee1-rescued cells display very high levels of mitotic cdc2 kinase activity. We account for this anomaly by our observation that the cdc2 activator, cdc25C, is a cytoplasmic protein that, like cyclin B1, enters the nucleus at the G2/M transition. Thus, cdc2 is likely to be activated in the cytoplasm and requires nuclear localization to initiate both cytoplasmic and nuclear mitotic transformations. The human wee1 kinase appears to coordinate the transition between DNA replication and mitosis by protecting the nucleus from this cytoplasmically activated cdc2 kinase.
Heald
R
R
Department of Cellular and Molecular Physiology, Harvard Medical School, Boston, Massachusetts 02115.
McLoughlin
M
M
McKeon
F
F
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal; D001483:Base Sequence; D016203:CDC2 Protein Kinase / Q000378:metabolism*; D018797:Cell Cycle Proteins; D002460:Cell Line; D002467:Cell Nucleus / Q000502:physiology*; D006224:Cricetinae; D016213:Cyclins / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics; D003593:Cytoplasm / Q000201:enzymology; D004261:DNA Replication; D004789:Enzyme Activation; D005455:Fluorescent Antibody Technique; D006367:HeLa Cells; D006801:Humans; D007668:Kidney; D008938:Mitosis / Q000502:physiology*; D008954:Models, Biological; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D009838:Oligodeoxyribonucleotides; D010957:Plasmids; D011494:Protein Kinases / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases; D029702:Schizosaccharomyces pombe Proteins; D008941:Spindle Apparatus / Q000502:physiology / Q000648:ultrastructure; D014162:Transfection
D000911:Antibodies, Monoclonal; D018797:Cell Cycle Proteins; D016213:Cyclins; D009687:Nuclear Proteins; D009838:Oligodeoxyribonucleotides; D029702:Schizosaccharomyces pombe Proteins; D011494:Protein Kinases; C068689:wee1 protein, S pombe; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; D016203:CDC2 Protein Kinase