Calmodulin protects Aurora B on the midbody to regulate the fidelity of cytokinesis.
Aurora B kinase is an integral regulator of cytokinesis as it stabilizes the intercellular canal within the midbody to ensure proper chromosomal segregation during cell division. Here we identified an E3 ligase subunit, F box protein FBXL2, that by recognizing a calmodulin binding signature within Aurora B, ubiquitinates and removes the kinase from the midbody. Calmodulin, by competing with the F box protein for access to the calmodulin binding signature, protected Aurora B from FBXL2. Calmodulin co-localized with Aurora B on the midbody, preserved Aurora B levels in cells, and stabilized intercellular canals during delayed abscission. Genetic or pharmaceutical depletion of endogenous calmodulin significantly reduced Aurora B protein levels at the midbody resulting in tetraploidy and multi-spindle formation. The calmodulin inhibitor, calmidazolium, reduced Aurora B protein levels resulting in tetraploidy, mitotic arrest, and apoptosis of tumorigenic cells and profoundly inhibiting tumor formation in athymic nude mice. These observations indicate molecular interplay between Aurora B and calmodulin in telophase and suggest that calmodulin acts as a checkpoint sensor for chromosomal segregation errors during mitosis.
Department of Medicine, The University of Pittsburgh, Pittsburgh, PA, USA.
Rama K
RK
Mallampalli
Jennifer R
JR
Glasser
Tiffany A
TA
Coon
Bill B
BB
Chen
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D064107:Aurora Kinase B; D064127:Aurora Kinases; D001665:Binding Sites; D002147:Calmodulin / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D020090:Chromosome Segregation / Q000187:drug effects; D048749:Cytokinesis / Q000187:drug effects / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D044783:F-Box Proteins / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013692:Telophase / Q000187:drug effects / Q000235:genetics*; D047368:Tumor Burden / Q000187:drug effects
D002147:Calmodulin; D004791:Enzyme Inhibitors; D044783:F-Box Proteins; C558726:FBXL2 protein, mouse; D007093:Imidazoles; C031938:calmidazolium; C576921:AURKB protein, human; C576924:Aurkb protein, mouse; D064107:Aurora Kinase B; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases
Aurora B; FBXL2; calmodulin; midbody; mitosis