PKCɛ switches Aurora B specificity to exit the abscission checkpoint

Pike, Tanya; Brownlow, Nicola; Kjær, Svend; Carlton, Jeremy G.; Parker, Peter J.

doi:10.1038/ncomms13853

Cited by 24 publications

(31 citation statements)

References 29 publications

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“…Here, we identify RIF1 and its binding partner, protein phosphatase 1 (PP1), as being critical for regulation of abscission timing in human cells. We show that RIF1 promotes cytokinesis through recruitment of PP1 to the midbody, which then counteracts Aurora B kinase activity, leading to dephosphorylation of a regulator of abscission timing, CHMP4C [6][7][8][9][10]. Although RIF1 binds to unresolved DNA bridges that persist into telophase [11], we show that this cytokinetic function of the RIF1-PP1 axis is not limited to instances where cell division is perturbed by the presence of bridges.…”

Section: Discussionmentioning

confidence: 89%

The RIF1-PP1 Axis Controls Abscission Timing in Human Cells

et al. 2019

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Section: Discussionmentioning

confidence: 89%

The RIF1-PP1 Axis Controls Abscission Timing in Human Cells

et al. 2019

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“…PKCε phosphorylates AURKB at Ser227 which alters the substrate selectivity of AURKB towards a particular set of substrates, and this switch is essential for the completion of cell division after the abscission checkpoint 32 . AURKB Ser227 is equivalent to AURKC Ser193 (Fig.…”

Section: Discussionmentioning

confidence: 99%

Structural mechanism of synergistic activation of Aurora kinase B/C by phosphorylated INCENP

Azeez

Chatterjee

et al. 2019

Nat Commun

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Aurora kinases B and C (AURKB/AURKC) are activated by binding to the C-terminal domain of INCENP. Full activation requires phosphorylation of two serine residues of INCENP that are conserved through evolution, although the mechanism of this activation has not been explained. Here we present crystal structures of the fully active complex of AURKC bound to INCENP, consisting of phosphorylated, activated, AURKC and INCENP phosphorylated on its TSS motif, revealing the structural and biochemical mechanism of synergistic activation of AURKC:INCENP. The structures show that TSS motif phosphorylation stabilises the kinase activation loop of AURKC. The TSS motif phosphorylations alter the substrate-binding surface consistent with a mechanism of altered kinase substrate selectivity and stabilisation of the protein complex against unfolding. We also analyse the binding of the most specific available AURKB inhibitor, BRD-7880, and demonstrate that the well-known Aurora kinase inhibitor VX-680 disrupts binding of the phosphorylated INCENP TSS motif.

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“…INCENPb becomes chronologically critical for the localization and activity of Aurora B on the central spindle and midbody. A comparative proteomics analysis has shown that Aurora B dramatically switches its binding partners in the mitosis to cytokinesis transition, with many involved in microtubule binding and cytoskeleton organization [52,53]. Intermediate filaments such as vimentin, GRAP (glial fibrillary acidic protein) and desmin are components of intercellular bridges, and phosphorylation by Aurora B can lead to their disassembly [54].…”

Section: Incenpb Is Critical For the Localization And Activity Of Aurmentioning

confidence: 99%

Switching of INCENP paralogs controls transitions in mitotic chromosomal passenger complex functions

et al. 2019

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A single inner centromere protein (INCENP) found throughout eukaryotes modulates Aurora B kinase activity and chromosomal passenger complex (CPC) localization, which is essential for timely mitotic progression. It has been proposed that INCENP might act as a rheostat to regulate Aurora B activity through mitosis, with successively higher activity threshold levels for chromosome alignment, the spindle checkpoint, anaphase spindle transfer and finally spindle elongation and cytokinesis. It remains mechanistically unclear how this would be achieved. Here, we reveal that the urochordate, Oikopleura dioica, possesses two INCENP paralogs, which display distinct localizations and subfunctionalization in order to complete M-phase. INCENPa was localized on chromosome arms and centromeres by prometaphase, and modulated Aurora B activity to mediate H3S10/S28 phosphorylation, chromosome condensation, spindle assembly and transfer of the CPC to the central spindle. Polo-like kinase (Plk1) recruitment to CDK1 phosphorylated INCENPa was crucial for INCENPa-Aurora B enrichment on centromeres. The second paralog, INCENPb was enriched on centromeres from prometaphase, and relocated to the central spindle at anaphase onset. In the absence of INCENPa, meiotic spindles failed to form, and homologous chromosomes did not segregate. INCENPb was not required for early to mid M-phase events but became essential for the activity and localization of Aurora B on the central spindle and midbody during cytokinesis in order to allow abscission to occur. Together, our results demonstrate that INCENP paralog switching on centromeres modulates Aurora B kinase localization, thus chronologically regulating CPC functions during fast embryonic divisions in the urochordate O. dioica.

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PKCɛ switches Aurora B specificity to exit the abscission checkpoint

Cited by 24 publications

References 29 publications

The RIF1-PP1 Axis Controls Abscission Timing in Human Cells

The RIF1-PP1 Axis Controls Abscission Timing in Human Cells

Structural mechanism of synergistic activation of Aurora kinase B/C by phosphorylated INCENP

Switching of INCENP paralogs controls transitions in mitotic chromosomal passenger complex functions

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