Spatial Compartmentalization Specializes the Function of Aurora A and Aurora B

Li, Si; Deng, Zhaoxuan; Fu, Jingyan; Xu, Caiyue; Xin, Guangwei; Wu, Zhongqi; Luo, Jia; Wang, Gang; Zhang, Shuli; Zhang, Boyan; Zou, Fangdong; Jiang, Qing; Zhang, Chuanmao

doi:10.1074/jbc.m115.652453

Cited by 40 publications

(35 citation statements)

References 48 publications

(48 reference statements)

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“…As the kinases share nearly identical consensus target motifs [22], it is likely that the principal determinant of their substrate specificity is their respective sub-cellular localizations [23]. Here, we investigate whether a non-CEN-based pathway contributes to error correction by testing the hypothesis that AAK phosphorylates kinetochore substrates in the vicinity of poles.…”

Section: Resultsmentioning

confidence: 99%

Aurora A Kinase Contributes to a Pole-Based Error Correction Pathway

et al. 2015

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Summary Chromosome biorientation, where sister kinetochores attach to microtubules (MTs) from opposing spindle poles, is the configuration that best ensures equal partitioning of the genome during cell division. Erroneous kinetochore-microtubule (kt-MT) attachments are commonplace but often corrected prior to anaphase [1, 2]. Error correction, thought to be mediated primarily by the centromere-enriched Aurora B kinase (ABK) [3-5], typically occurs near spindle poles [6]; albeit, the relevance of this locale is unclear. Furthermore, polar ejection forces (PEFs), highest near poles [7], can stabilize improper attachments by pushing mal-oriented chromosome arms away from spindle poles [8, 9]. Hence, a conundrum: erroneous kt-MT attachments are weakened where PEFs are most likely to strengthen them. Here, we report that Aurora A kinase (AAK) opposes the stabilizing effect of PEFs. AAK activity contributes to phosphorylation of kinetochore substrates near poles and its inhibition results in chromosome mis-alignment and an increased incidence of erroneous kt-MT attachments. Furthermore, AAK directly phosphorylates a site in the N-terminal tail of Ndc80/Hec1 that has been implicated in reducing the affinity of the Ndc80 complex for MTs when phosphorylated [10-12]. We propose that an AAK activity gradient contributes to correcting mal-oriented kt-MT attachments in the vicinity of spindle poles.

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Section: Resultsmentioning

confidence: 99%

Aurora A Kinase Contributes to a Pole-Based Error Correction Pathway

et al. 2015

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“…In agreement with previous findings that AURKB mainly localizes at the inner centromere regions during prophase and subsequently relocalizes to the midzone of the central spindle and concentrates at the midbody (Adams et al, 2000;Kaitna et al, 2000;Terada et al, 1998), and that its catalytically inactive mutant K106R fails to drive cell segregation during mitosis (Honda et al, 2003), we observed that the ectopically expressed WT AURKB, instead of its K106R mutant, presents the expected relocalization from centromeres to the central spindle. Although several previous studies have shown that the function between AURKA and AURKB could be converted by manipulating their different localizations or even single amino acid change (Fu et al, 2009;Hans et al, 2009;Li et al, 2015), the cause of their conversion in physiological relevance remains to be investigated. In this study, we observed punctate signals of exogenous AURKB distributed in the poles of cells coexpressing LANA, as well as the spindle pole localization of endogenous AURKB forms in BCBL1 cells during mitosis, which is distinct from the typical distribution of AURKB.…”

Section: Discussionmentioning

confidence: 99%

Viral-Mediated AURKB Cleavage Promotes Cell Segregation and Tumorigenesis

Zhu

Ding

et al. 2019

Cell Reports

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“…The Aurora-A and -B kinases have been shown to phosphorylate common substrates at the same sites [2, 4, 22, 23, 38]. However, whether the sites of Haspin phosphorylated by Aurora-A and Aurora-B are the same need to be further confirmed.…”

Section: Discussionmentioning

confidence: 99%

Aurora-A promotes the establishment of spindle assembly checkpoint by priming the Haspin-Aurora-B feedback loop in late G2 phase

Jiang

et al. 2017

Cell Discov

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Aurora-A kinase functions mainly in centrosome maturation, separation and spindle formation. It has also been found to be amplified or overexpressed in a range of solid tumors, which is linked with tumor progression and poor prognosis. Importantly, Aurora-A inhibitors are being studied in a number of ongoing clinical trials. However, whether and how Aurora-A has a role in the regulation of the mitotic checkpoint is controversial. Additionally, the function of nuclear-accumulated Aurora-A in late G2 phase is not clear. Here we show that knockout, inhibition or blockade of the nuclear entry of Aurora-A severely decreased the centromere localization of Aurora-B and the phosphorylation of histone H3 threonine 3 (H3T3-ph) mediated by the kinase Haspin in late G2 phase. We further reveal that nuclear-accumulated Aurora-A phosphorylates Haspin at multiple sites at its N-terminus and that this promotes H3T3-ph and the rapid recruitment to the centromere of the chromosomal passenger complex. In addition, Aurora-A facilitates the association of Aurora-B with their common substrates: Haspin and Plk1. Notably, these functions of Aurora-A are mostly independent of Plk1. Thus we demonstrate that, in late G2 and prophase, Aurora-A phosphorylates Haspin to trigger the Haspin-H3T3-ph-Aurora-B positive feedback loop that supports the timely establishment of the chromosomal passenger complex and the mitotic checkpoint before spindle assembly.

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Spatial Compartmentalization Specializes the Function of Aurora A and Aurora B

Cited by 40 publications

References 48 publications

Aurora A Kinase Contributes to a Pole-Based Error Correction Pathway

Aurora A Kinase Contributes to a Pole-Based Error Correction Pathway

Viral-Mediated AURKB Cleavage Promotes Cell Segregation and Tumorigenesis

Aurora-A promotes the establishment of spindle assembly checkpoint by priming the Haspin-Aurora-B feedback loop in late G2 phase

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