Autoinhibition and Polo-Dependent Multisite Phosphorylation Restrict Activity of the Histone H3 Kinase Haspin to Mitosis

Ghenoiu, Cristina; Wheelock, Michael; Funabiki, Hironori

doi:10.1016/j.molcel.2013.10.002

Cited by 77 publications

(103 citation statements)

References 38 publications

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“…PLK1 is overexpressed in many human tumors and is associated with tumorigenesis (15). It has been recently reported that PLK1 phosphorylates the N terminus of Haspin, leading to its activation and resulting in the phosphorylation of the threonine 3 on histone H3 tail (H3T3) (16,17). Then H3pT3 is recognized by the chromosome passenger complex, resulting in cluster-mediated autophosphorylation and autoactivation of Aurora B (18,19).…”

mentioning

confidence: 99%

Phosphorylation of PP1 Regulator Sds22 by PLK1 Ensures Accurate Chromosome Segregation

Duan

Wang²,

Wang

et al. 2016

Journal of Biological Chemistry

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During cell division, accurate chromosome segregation is tightly regulated by Polo-like kinase 1 (PLK1) and opposing activities of Aurora B kinase and protein phosphatase 1 (PP1). However, the regulatory mechanisms underlying the aforementioned hierarchical signaling cascade during mitotic chromosome segregation have remained elusive. Sds22 is a conserved regulator of PP1 activity, but how it regulates PP1 activity in space and time during mitosis remains elusive. Here we show that Sds22 is a novel and cognate substrate of PLK1 in mitosis, and the phosphorylation of Sds22 by PLK1 elicited an inhibition of PP1-mediated dephosphorylation of Aurora B at threonine 232 (Thr 232 ) in a dose-dependent manner. Overexpression of a phosphomimetic mutant of Sds22 causes a dramatic increase in mitotic delay, whereas overexpression of a non-phosphorylatable mutant of Sds22 results in mitotic arrest. Mechanistically, the phosphorylation of Sds22 by PLK1 strengthens the binding of Sds22 to PP1 and inhibits the dephosphorylation of Thr 232 of Aurora B to ensure a robust, error-free metaphase-anaphase transition. These findings delineate a conserved signaling hierarchy that orchestrates dynamic protein phosphorylation and dephosphorylation of critical mitotic regulators during chromosome segregation to guard chromosome stability.

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mentioning

confidence: 99%

Phosphorylation of PP1 Regulator Sds22 by PLK1 Ensures Accurate Chromosome Segregation

Duan

Wang²,

Wang

et al. 2016

Journal of Biological Chemistry

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“…This auto-inhibition is released through Cdk1 phosphorylation of Haspin N-terminus followed by the recruitment of Plk1 on the Cdk1 phospho-site and its activation. Activated Plk1 phosphorylates several sites on Haspin N-terminus releasing its activity in a timely manner at the beginning of mitosis triggering H3T3 phosphorylation and CPC recruitment at centromeres [47,48]. Furthermore, Wang et al showed that Aurora B further phosphorylates Haspin Nterminus enhancing its ability to generate H3T3 phospho-sites for Survivin/CPC binding [49] ( Figure 5 lower panel).…”

Section: Regulation Of Haspin Activitymentioning

confidence: 99%

“…However, it is highly phosphorylated during mitosis [13]. Phosphoproteomic studies showed that these phosphorylations are on the N-terminal domain of the protein, where phosphorylation consensus sites for Cdk1, Plk1, and Aurora B are present [45][46][47]. Phosphoryation events on the N-terminal domain at the onset of mitosis trigger conformational changes and influence Haspin kinetics parameters (see above).…”

Section: Regulation Of Haspin Activitymentioning

confidence: 99%

“…Haspin phosphorylation by Cdk1/cyclin B starts on T128 of human Haspin (T206 in Xenopus laevis) [47,48]. Gheniou et al showed that Xenopus Haspin auto-inhibits itself during interphase through a conserved basic site in its N-terminus part close to its kinase domain [47].…”

Section: Regulation Of Haspin Activitymentioning

confidence: 99%

“…Gheniou et al showed that Xenopus Haspin auto-inhibits itself during interphase through a conserved basic site in its N-terminus part close to its kinase domain [47]. This auto-inhibition is released through Cdk1 phosphorylation of Haspin N-terminus followed by the recruitment of Plk1 on the Cdk1 phospho-site and its activation.…”

Section: Regulation Of Haspin Activitymentioning

confidence: 99%

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The Mitotic Protein Kinase Haspin and Its Inhibitors

Feizbakhsh¹,

Place²,

Fant³

et al. 2017

Protein Phosphorylation

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Haspin is an atypical serine/threonine protein kinase essential to mitosis. Unlike other protein kinases, its kinase domain does not require phosphorylation in order to be activated and bears very high substrate specificity and selectivity. Few substrates have been identified so far. Haspin phosphorylation on threonine 3 of Histone H3 from prophase to anaphase participates to centromeric Aurora B localization and ensures proper kinetochore-microtubule attachment. Haspin is also involved in the maintenance of centromeric cohesion and the mitotic spindle. Inhibitors have been developed and provided tools to dissect Haspin function. The kinase is now considered as a potential therapeutic target against cancer. We discuss here the latest findings on this essential mitotic protein.

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Orchestration of the spindle assembly checkpoint by CDK1‐cyclin B1

2019

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In mitosis, the spindle assembly checkpoint (SAC) monitors the formation of microtubule‐kinetochore attachments during capture of chromosomes by the mitotic spindle. Spindle assembly is complete once there are no longer any unattached kinetochores. Here, we will discuss the mechanism and key components of spindle checkpoint signalling. Unattached kinetochores bind the principal spindle checkpoint kinase monopolar spindle 1 (MPS1). MPS1 triggers the recruitment of other spindle checkpoint proteins and the formation of a soluble inhibitor of anaphase, thus preventing exit from mitosis. On microtubule attachment, kinetochores become checkpoint silent due to the actions of PP2A‐B56 and PP1. This SAC responsive period has to be coordinated with mitotic spindle formation to ensure timely mitotic exit and accurate chromosome segregation. We focus on the molecular mechanisms by which the SAC permissive state is created, describing a central role for CDK1‐cyclin B1 and its counteracting phosphatase PP2A‐B55. Furthermore, we discuss how CDK1‐cyclin B1, through its interaction with MAD1, acts as an integral component of the SAC, and actively orchestrates checkpoint signalling and thus contributes to the faithful execution of mitosis.

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Autoinhibition and Polo-Dependent Multisite Phosphorylation Restrict Activity of the Histone H3 Kinase Haspin to Mitosis

Cited by 77 publications

References 38 publications

Phosphorylation of PP1 Regulator Sds22 by PLK1 Ensures Accurate Chromosome Segregation

Phosphorylation of PP1 Regulator Sds22 by PLK1 Ensures Accurate Chromosome Segregation

The Mitotic Protein Kinase Haspin and Its Inhibitors

Orchestration of the spindle assembly checkpoint by CDK1‐cyclin B1

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