Evidence toward a Dual Phosphatase Mechanism That Restricts Aurora A (Thr-295) Phosphorylation during the Early Embryonic Cell Cycle

Kang, Qing; Srividhya, Jeyaraman; Ipe, Joseph; Pomerening, Joseph R.

doi:10.1074/jbc.m113.527622

Cited by 6 publications

(3 citation statements)

References 59 publications

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“…AURKA is degraded at the end of mitosis 58 and thus must be resynthesized during interphase of the next cell cycle. Once translated, AURKA auto-phosphorylates on its own T-loop but this activity is counteracted by the PP1 and PP2A phosphatases in interphase 43 , 59 , 60 and by PP6 while bound to Tpx2 during mitosis 61 . As dephosphorylation maintains AURKA in an inactive state, the crucial question arises as to how AURKA overcomes the repressive effect of PPases to drive mitotic commitment.…”

Section: Discussionmentioning

confidence: 99%

Bora phosphorylation substitutes in trans for T-loop phosphorylation in Aurora A to promote mitotic entry

et al. 2021

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Polo-like kinase 1 (Plk1) is instrumental for mitotic entry and progression. Plk1 is activated by phosphorylation on a conserved residue Thr210 in its activation segment by the Aurora A kinase (AURKA), a reaction that critically requires the co-factor Bora phosphorylated by a CyclinA/B-Cdk1 kinase. Here we show that phospho-Bora is a direct activator of AURKA kinase activity. We localize the key determinants of phospho-Bora function to a 100 amino acid region encompassing two short Tpx2-like motifs and a phosphoSerine-Proline motif at Serine 112, through which Bora binds AURKA. The latter substitutes in trans for the Thr288 phospho-regulatory site of AURKA, which is essential for an active conformation of the kinase domain. We demonstrate the importance of these determinants for Bora function in mitotic entry both in Xenopus egg extracts and in human cells. Our findings unveil the activation mechanism of AURKA that is critical for mitotic entry.

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Section: Discussionmentioning

confidence: 99%

Bora phosphorylation substitutes in trans for T-loop phosphorylation in Aurora A to promote mitotic entry

et al. 2021

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“…While RepoMan’s ability to interact with chromatin is reduced by Aurora B-mediated phosphorylation of S893 [23], interaction with PP1 is diminished by CDK1/cyclin B-mediated phosphorylation at T412 and probably further sites at S400 and T419 [24,25]. On the other hand, phosphatases can also restrict kinase activity by removal of phosphates from the activation loop [48,49], or they even trigger kinase activity as exemplified by CDC25A, which removes an inhibitory phosphorylation from CDK1 [50].…”

Section: Discussionmentioning

confidence: 99%

The Aurora B-controlled PP1/RepoMan complex determines the spatial and temporal distribution of mitotic H2B S6 phosphorylation

Pfisterer,

Robert,

Saul

et al. 2024

Open Biol.

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The precise spatial and temporal control of histone phosphorylations is important for the ordered progression through the different phases of mitosis. The phosphorylation of H2B at S6 (H2B S6ph), which is crucial for chromosome segregation, reaches its maximum level during metaphase and is limited to the inner centromere. We discovered that the temporal and spatial regulation of this modification, as well as its intensity, are governed by the scaffold protein RepoMan and its associated catalytically active phosphatases, PP1α and PP1γ. Phosphatase activity is inhibited at the area of maximal H2B S6 phosphorylation at the inner centromere by site-specific Aurora B-mediated inactivation of the PP1/RepoMan complex. The motor protein Mklp2 contributes to the relocalization of Aurora B from chromatin to the mitotic spindle during anaphase, thus alleviating Aurora B-dependent repression of the PP1/RepoMan complex and enabling dephosphorylation of H2B S6. Accordingly, dysregulation of Mklp2 levels, as commonly observed in tumour cells, leads to the lack of H2B S6 dephosphorylation during early anaphase, which might contribute to chromosomal instability.

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“…Many of these proteins have also been shown to be regulated by Cdk1-dependent mitotic phosphorylations. That subset includes Eg5, NuMA, MCAK, Kif4a, Aurora-A, and TPX2 [52][53][54][55][56][57]; NuMA, and TPX2 have also been shown to be substrates of PP2A-B55d [58], PP2A [59], and other phosphatases. We posit that the addition of cyclin B1 dm alone is not sufficient to accurately recapitulate the level of mitotic phosphorylation of one (or more) of these proteins and that proper phosphorylation is only achieved when the cyclin is added in combination with rArpp19.…”

Section: The Relationship Between Gwl Activity and Spindle Bipolaritymentioning

confidence: 99%

Induction of a Spindle-Assembly-Competent M Phase in Xenopus Egg Extracts

2019

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Evidence toward a Dual Phosphatase Mechanism That Restricts Aurora A (Thr-295) Phosphorylation during the Early Embryonic Cell Cycle

Cited by 6 publications

References 59 publications

Bora phosphorylation substitutes in trans for T-loop phosphorylation in Aurora A to promote mitotic entry

Bora phosphorylation substitutes in trans for T-loop phosphorylation in Aurora A to promote mitotic entry

The Aurora B-controlled PP1/RepoMan complex determines the spatial and temporal distribution of mitotic H2B S6 phosphorylation

Induction of a Spindle-Assembly-Competent M Phase in Xenopus Egg Extracts

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