Function and regulation of Aurora/Ipl1p kinase family in cell division

Yu, Ke; Dou, Zhen; Zhang, Jie; Yao, Xue Biao

doi:10.1038/sj.cr.7290152

Cited by 61 publications

(37 citation statements)

References 71 publications

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“…Proper chromosome segregation requires a faithful physical link between spindle microtubules and centromeric DNA via a protein supercomplex called kinetochore (Cleveland et al, 2003). In addition to providing a physical link between chromosomes and spindle microtubules, the kinetochore has an active function in orchestrating chromosome movements through microtubule motors and correcting spindle microtubule attachment to kinetochore via checkpoint sensors located at or near it (Yao et al, 2000;Ke et al, 2003;Fang and Fang 2007). Recent studies show that CIN results from high incidence of aberrant kinetochore microtubule attachments such as syntelic attachment (Storchova et al, 2006), which promotes tumorigenesis in p53-null cells (Fujiwara et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

“…The key switch for the onset of mitosis is the archetypal cyclin-dependent kinase, Cdc2. Besides Cdc2, there are three protein serine/ threonine kinase families, the Polo kinases, Aurora kinases and the never in mitosis A-related kinases (NEK) (Nigg, 2001;Fry 2002;Ke et al, 2003), which participates in mitotic progression. Aneuploidy and chromosome instability are two of the most common abnormalities in cancer cells, which arise from aberrant chromosome segregation during mitosis.…”

Section: Introductionmentioning

confidence: 99%

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The mitotic checkpoint kinase NEK2A regulates kinetochore microtubule attachment stability

Cai

Yao

et al. 2008

Oncogene

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Loss or gain of whole chromosome, the form of chromosome instability commonly associated with cancers is thought to arise from aberrant chromosome segregation during cell division. Chromosome segregation in mitosis is orchestrated by the interaction of kinetochores with spindle microtubules. Our studies show that NEK2A is a kinetochore-associated protein kinase essential for faithful chromosome segregation. However, it was unclear how NEK2A ensures accurate chromosome segregation in mitosis. Here we show that NEK2A-mediated Hec1 (highly expressed in cancer) phosphorylation is essential for faithful kinetochore microtubule attachments in mitosis. Using phospho-specific antibody, our studies show that NEK2A phosphorylates Hec1 at Ser165 during mitosis. Although such phosphorylation is not required for assembly of Hec1 to the kinetochore, expression of non-phosphorylatable mutant Hec1 S165 perturbed chromosome congression and resulted in a dramatic increase in microtubule attachment errors, including syntelic and monotelic attachments. Our in vitro reconstitution experiment demonstrated that Hec1 binds to microtubule in low affinity and phosphorylation by NEK2A, which prevents aberrant kinetochore-microtubule connections in vivo, increases the affinity of the Ndc80 complex for microtubules in vitro. Thus, our studies illustrate a novel regulatory mechanism in which NEK2A kinase operates a faithful chromosome attachment to spindle microtubule, which prevents chromosome instability during cell division.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The mitotic checkpoint kinase NEK2A regulates kinetochore microtubule attachment stability

Cai

Yao

et al. 2008

Oncogene

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“…Other mitotic kinases take part in execution of specific mitotic events in close association with the Cdk activity. It is interesting that a single mitotic kinase is often involved in multiple cellular processes during mitosis (Ke et al, 2003). For example, aurora B is a kinase for histone H3 whose phosphorylation is critical for chromosome condensation and/or segregation (Hsu et al, 2000;Giet and Glover, 2001).…”

Section: Introductionmentioning

confidence: 99%

Suppression ofNek2Ain mouse early embryos confirms its requirement for chromosome segregation

Sonn

Khang

Kim

et al. 2004

Journal of Cell Science

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Nek2, a mammalian structural homologue of Aspergillus protein kinase NIMA, is predominantly known as a centrosomal kinase that controls centriole-centriole linkage during the cell cycle. However, its dynamic subcellular localization during mitosis suggested that Nek2 might be involved in diverse cell cycle events in addition to the centrosomal cycle. In order to determine the importance of Nek2 during mammalian development, we investigated the expression and function of Nek2 in mouse early embryos. Our results show that both Nek2A and Nek2B were expressed throughout early embryogenesis. Unlike cultured human cells, however, embryonic Nek2A appeared not to be destroyed upon entry into mitosis, suggesting that the Nek2A protein level is controlled in a unique manner during mouse early embryogenesis. Suppression of Nek2 expression by RNAi resulted in developmental defects at the second mitosis. Many of the blastomeres in Nek2-suppressed embryos showed abnormality in nuclear morphology, including dumbbell-like nuclei, nuclear bridges and micronuclei. These results indicate the importance of Nek2 for proper chromosome segregation in embryonic mitoses.

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“…Over-expression of Aurora-A disrupt the assembly of the mitotic checkpoint complex that leads to the genetic instability and tumorigenesis. 23 Dysregulation of Aurora-A is thought to be oncogenic and resulted in the production of multiple centrosomes and aneuploidy. 18,24 Aurora-A selective inhibition results in mitosis accumulation and abnormalities in centrosome separation leading to the formation of monopolar spindles.…”

Section: -13mentioning

confidence: 99%

Pharmacophore Modeling and Molecular Dynamics Simulation to Find the Potent Leads for Aurora Kinase B

Sakkiah¹,

Thangapandian²,

Kim³

et al. 2012

Bulletin of the Korean Chemical Society

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Identification of the selective chemical features for Aurora-B inhibitors gained much attraction in drug discovery for the treatment of cancer. Hence to identify the Aurora-B critical features various techniques were utilized such as pharmacophore generation, virtual screening, homology modeling, molecular dynamics, and docking. Top ten hypotheses were generated for Aurora-B and Aurora-A. Among ten hypotheses, HypoB1 and HypoA1 were selected as a best hypothesis for Aurora-B and Aurora-A based on cluster analysis and ranking score, respectively. Test set result revealed that ring aromatic (RA) group in HypoB1 plays an essential role in differentiates Aurora-B from Aurora-A inhibitors. Hence, HypoB1 used as 3D query in virtual screening of databases and the hits were sorted out by applying drug-like properties and molecular docking. The molecular docking result revealed that 15 hits have shown strong hydrogen bond interactions with Ala157, Glu155, and Lys106. Hence, we proposed that HypoB1 might be a reasonable hypothesis to retrieve the structurally diverse and selective leads from various databases to inhibit Aurora-B.

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Function and regulation of Aurora/Ipl1p kinase family in cell division

Cited by 61 publications

References 71 publications

The mitotic checkpoint kinase NEK2A regulates kinetochore microtubule attachment stability

The mitotic checkpoint kinase NEK2A regulates kinetochore microtubule attachment stability

Suppression ofNek2Ain mouse early embryos confirms its requirement for chromosome segregation

Pharmacophore Modeling and Molecular Dynamics Simulation to Find the Potent Leads for Aurora Kinase B

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