Cell cycle regulation of central spindle assembly.
The bipolar mitotic spindle is responsible for segregating sister chromatids at anaphase. Microtubule motor proteins generate spindle bipolarity and enable the spindle to perform mechanical work. A major change in spindle architecture occurs at anaphase onset when central spindle assembly begins. This structure regulates the initiation of cytokinesis and is essential for its completion. Central spindle assembly requires the centralspindlin complex composed of the Caenorhabditis elegans ZEN-4 (mammalian orthologue MKLP1) kinesin-like protein and the Rho family GAP CYK-4 (MgcRacGAP). Here we describe a regulatory mechanism that controls the timing of central spindle assembly. The mitotic kinase Cdk1/cyclin B phosphorylates the motor domain of ZEN-4 on a conserved site within a basic amino-terminal extension characteristic of the MKLP1 subfamily. Phosphorylation by Cdk1 diminishes the motor activity of ZEN-4 by reducing its affinity for microtubules. Preventing Cdk1 phosphorylation of ZEN-4/MKLP1 causes enhanced metaphase spindle localization and defects in chromosome segregation. Thus, phosphoregulation of the motor domain of MKLP1 kinesin ensures that central spindle assembly occurs at the appropriate time in the cell cycle and maintains genomic stability.
Research Institute of Molecular Pathology, Dr. Bohrgasse 7, A-1030 Vienna, Austria.
Masanori
M
Mishima
Visnja
V
Pavicic
Ulrike
U
Grüneberg
Erich A
EA
Nigg
Michael
M
Glotzer
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000595:Amino Acid Sequence; D000705:Anaphase; D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000166:cytology* / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000502:physiology*; D020090:Chromosome Segregation; D002875:Chromosomes / Q000378:metabolism; D017124:Conserved Sequence; D019926:Cyclin B / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D016547:Kinesins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism; D020409:Molecular Motor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D008941:Spindle Apparatus / Q000737:chemistry / Q000378:metabolism*; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism
D029742:Caenorhabditis elegans Proteins; D019926:Cyclin B; C092935:KIF23 protein, human; C490517:MKLP1 protein, C elegans; D008869:Microtubule-Associated Proteins; D020409:Molecular Motor Proteins; D014404:Tubulin; C114455:ZEN-4 protein, C elegans; D016203:CDC2 Protein Kinase; D010749:Phosphoprotein Phosphatases; C489137:cdc-14 protein, C elegans; D000251:Adenosine Triphosphatases; D016547:Kinesins