The role of mitotic kinases in coupling the centrosome cycle with the assembly of the mitotic spindle

Abstract

The centrosome acts as the major microtubule-organizing center (MTOC) for cytoskeleton maintenance in interphase and mitotic spindle assembly in vertebrate cells. It duplicates only once per cell cycle in a highly spatiotemporally regulated manner. When the cell undergoes mitosis, the duplicated centrosomes separate to define spindle poles and monitor the assembly of the bipolar mitotic spindle for accurate chromosome separation and the maintenance of genomic stability. However, centrosome abnormalities occur frequently and often lead to monopolar or multipolar spindle formation, which results in chromosome instability and possibly tumorigenesis. A number of studies have begun to dissect the role of mitotic kinases, including NIMA-related kinases (Neks), cyclindependent kinases (CDKs), Polo-like kinases (Plks) and Aurora kinases, in regulating centrosome duplication, separation and maturation and subsequent mitotic spindle assembly during cell cycle progression. In this Commentary, we review the recent research progress on how these mitotic kinases are coordinated to couple the centrosome cycle with the cell cycle, thus ensuring bipolar mitotic spindle fidelity. Understanding this process will help to delineate the relationship between centrosomal abnormalities and spindle defects.

Novel STIL Compound Heterozygous Mutations Cause Severe Fetal Microcephaly and Centriolar Lengthening

“…In the last years, the implementation of massively parallel sequencing in both research and medical practice contributed significantly to the acceleration in the identification of disease-associated genes, especially for rare and clinically heterogeneous mendelian disorders [Gilissen et al, 2011;Dixon-Salazar et al, 2012;Need et al, 2012;Rabbani et al, 2012Rabbani et al, , 2014Yang et al, 2013Yang et al, , 2014Wang et al, 2014]. Although the interpretation of the clinical significance and pathogenicity of variants identified by whole exome (WES)/genome sequencing is often challenging [Richards et al, 2015;Amendola et al, 2016], these technologies allowed researchers to determine the underlying developmental and molecular processes disrupted in many neurodevelopmental disorders, improving the clinical management as well as genetic counseling [Green and Guyer, 2011;Soden et al, 2014;MorrisRosendahl and Kaindl, 2015].…”

Primary Cilium-Mediated Crosstalk of Signaling Cascades in Ciliogenesis: Implications for Tumorigenesis and Senescence

“…During the G2 phase, daughter centrioles are matured and centrosomes are separated by a combination of interconnecting fiber break down, in a CDK1-Aur A-Plk1-Nek2A signaling cascade-dependent manner, and the inactivation of the interconnecting fiber-stabilizing molecule PP1c by CDK1. 134,135 Finally, bipolar spindle poles are formed by separated centrosomes for chromatin segregation in the mitotic phase. During the g1 phase, the mother centriole and duplicated centrioles are disengaged.…”

Aurora A inhibition by MNL8054 promotes centriole elongation during Drosophila male meiosis

“…34 The aur e209 and aur 287 alleles were reported in Glover et al 19 Flies were raised on standard Drosophila medium at 24 C.…”

“…To inhibit Aurora A, testes were incubated 24 hours in M3 medium containing 0.5 mM or 1 mM MLN8054 for 24 hours into a 24-well plate at 24 C. Incubation of testes in M3 medium containing DMSO but lacking MLN8054 had no effect on the structure of the centrioles.…”

“…18,22 These pleiotropic functions of Aurora A depend on the interaction with different proteins that may modulate its activity. 23,24 CALK, a distant Aurora A horthologue, has been reported to control the disassembly of the flagellar axoneme in Chlamydomonas after ionic stress, 25 suggesting that phosphorylation-based signaling may play a key role in the mechanism of axoneme microtubule depolymerisation. In mammalian cells, the resorption of the primary cilium depends by the interaction of Aurora A with HEF1, 26 Pitchfork, 27 and calmodulin, 28 to activate the histone deacetylase-6 (HDAC-6) and determine the depolymerisation of the axonemal microtubules.…”