Aurora-A and ch-TOG act in a common pathway in control of spindle pole integrity.
Mitotic spindle assembly is a highly regulated process, crucial to ensure the correct segregation of duplicated chromosomes in daughter cells and to avoid aneuploidy, a common feature of tumors. Among the most important spindle regulators is Aurora-A, a mitotic centrosomal kinase frequently overexpressed in tumors. Here, we investigated the role of Aurora-A in spindle pole organization in human cells. We show that RNA interference-mediated Aurora-A inactivation causes pericentriolar material fragmentation in prometaphase, yielding the formation of spindles with supernumerary poles. This fragmentation does not necessarily involve centrioles and requires microtubules (MTs). Aurora-A-depleted prometaphases mislocalize the MT-stabilizing protein colonic hepatic tumor-overexpressed gene (ch-TOG), which abnormally accumulates at spindle poles, as well as the mitotic centromere-associated kinesin (MCAK), the major functional antagonist of ch-TOG, which delocalizes from poles. ch-TOG is required for extrapole formation in prometaphases lacking Aurora-A, because co-depletion of Aurora-A and ch-TOG mitigates the fragmented pole phenotype. These results indicate a novel function of Aurora-A, the regulation of ch-TOG and MCAK localization, and highlight a common pathway involving the three factors in control of spindle pole integrity.
De Luca
M
M
Institute of Molecular Biology and Pathology, CNR, c/o University of Rome La Sapienza, Rome, Italy.
Brunetto
L
L
Asteriti
I A
IA
Giubettini
M
M
Lavia
P
P
Guarguaglini
G
G
D064127:Aurora Kinases; D006801:Humans; D016547:Kinesins / Q000378:metabolism; D008677:Metaphase / Q000187:drug effects; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D008938:Mitosis / Q000187:drug effects; D008954:Models, Biological; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D008941:Spindle Apparatus / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
C454180:CKAP5 protein, human; C091489:KIF2C protein, human; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D016547:Kinesins