Protein phosphatase 6 regulates mitotic spindle formation by controlling the T-loop phosphorylation state of Aurora A bound to its activator TPX2

Zeng, Kang; Bastos, Ricardo; Barr, Francis A.; Grüneberg, Ulrike

doi:10.1083/jcb.201008106

Cited by 170 publications

(252 citation statements)

References 66 publications

(117 reference statements)

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“…At present the basis for this driver effect remains unclear due to the lack of data on the consequence these mutations have for PP6 activity and the limited information about PP6 substrates. PP6 is reported to act in the regulation of NF-kappaB, DNA-dependant protein kinase (DNA-PK), histone c-H2AX and Aurora-A (Douglas et al, 2010;Mi et al, 2009;Stefansson and Brautigan, 2006;Zeng et al, 2010). However, it is not known if the action of PP6 on any of these substrates explains how the reported melanoma-associated changes in PPP6C promote tumour development.…”

Section: Introductionmentioning

confidence: 85%

Melanoma-associated mutations in protein phosphatase 6 cause chromosome instability and DNA damage due to dysregulated Aurora-A

Hammond

Zeng

Espert

et al. 2013

Journal of Cell Science

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SummaryMutations in the PPP6C catalytic subunit of protein phosphatase 6 (PP6) are drivers for the development of melanoma. Here, we analyse a panel of melanoma-associated mutations in PPP6C and find that these generally compromise assembly of the PP6 holoenzyme and catalytic activity towards a model substrate. Detailed analysis of one mutant, PPP6C-H114Y, in both primary melanoma and engineered cell lines reveals it is destabilized and undergoes increased proteasome-mediated turnover. Global analysis of phosphatase substrates by mass spectrometry identifies the oncogenic kinase Aurora-A as the major PP6 substrate that is dysregulated under these conditions. Accordingly, cells lacking PPP6C or carrying the PPP6C-H114Y allele have elevated Aurora-A kinase activity and display chromosome instability with associated Aurora-A-dependent micronucleation. Chromosomes mis-segregated to these micronuclei are preferentially stained by the DNA damage marker c-H2AX, suggesting that loss of PPP6C promotes both chromosome instability and DNA damage. These findings support the view that formation of micronuclei rather than chromosome instability alone explains how loss of PPP6C, and more generally mitotic spindle and centrosome defects, can act as drivers for genome instability in melanoma and other cancers.

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Section: Introductionmentioning

confidence: 85%

Melanoma-associated mutations in protein phosphatase 6 cause chromosome instability and DNA damage due to dysregulated Aurora-A

Hammond

Zeng

Espert

et al. 2013

Journal of Cell Science

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“…There could be a technical explanation for these observations, for example if the phosphorylated epitope is masked along spindle microtubules. Arguing against this is the fact that, in HeLa cells, phosphorylation of Aurora-A at the spindle becomes apparent in the absence of protein phosphatase 6 (the physiological phosphatase acting against Aurora-A) (22). It therefore seems likely that Aurora-A at spindle microtubules is not stably phosphorylated on Thr-288, but it remains to be confirmed whether the unphosphorylated Aurora-A is functional in human cells.…”

Section: Journal Of Biological Chemistrymentioning

confidence: 97%

Activation of Aurora-A Kinase by Protein Partner Binding and Phosphorylation Are Independent and Synergistic

Dodson¹,

Bayliss

2012

Journal of Biological Chemistry

126

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Background: Phosphorylation and TPX2 act together to stabilize the active conformation of Aurora-A. Results: TPX2 activates unphosphorylated Aurora-A, although phosphorylation makes a 2-fold greater energetic contribution to catalysis than TPX2. Conclusion: Either activator partially stabilizes the active conformation and stimulates kinase activity. Significance: Our revised model of kinase activation and mechanistic analysis might be applicable to other kinases.

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“…After nuclear envelope breakdown, TPX2 is released from importin-a/b-mediated inhibition in a RanGTP-dependent manner and then directly interacts with AurA to target it to spindle microtubules (Gruss et al, 2001;Kufer et al, 2002;Ö zlü et al, 2005;Tsai et al, 2003). Subsequently, TPX2 activates AurA by promoting the autophosphorylation of its T-loop Thr288 and preventing its PP1-mediated, but not PP6-mediated dephosphorylation (Bayliss et al, 2003;Eyers et al, 2003;Kufer et al, 2003;Zeng et al, 2010). Considering the fact that the RanGTP gradient that is established around the chromosome extensively contributes to spindle assembly and dynamics, it is conceivable that the formation of a secondary AurA-TPX2 gradient that contains active AurA and, consequently, its phosphorylated substrates is crucial for mitotic progression (Clarke and Zhang, 2008;Tsai et al, 2003).…”

Section: Roles Of Aurora a In Centrosome Maturation And Spindle Formamentioning

confidence: 99%

The role of mitotic kinases in coupling the centrosome cycle with the assembly of the mitotic spindle

Wang

Jiang

Zhang

2014

Journal of Cell Science

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The centrosome acts as the major microtubule-organizing center (MTOC) for cytoskeleton maintenance in interphase and mitotic spindle assembly in vertebrate cells. It duplicates only once per cell cycle in a highly spatiotemporally regulated manner. When the cell undergoes mitosis, the duplicated centrosomes separate to define spindle poles and monitor the assembly of the bipolar mitotic spindle for accurate chromosome separation and the maintenance of genomic stability. However, centrosome abnormalities occur frequently and often lead to monopolar or multipolar spindle formation, which results in chromosome instability and possibly tumorigenesis. A number of studies have begun to dissect the role of mitotic kinases, including NIMA-related kinases (Neks), cyclindependent kinases (CDKs), Polo-like kinases (Plks) and Aurora kinases, in regulating centrosome duplication, separation and maturation and subsequent mitotic spindle assembly during cell cycle progression. In this Commentary, we review the recent research progress on how these mitotic kinases are coordinated to couple the centrosome cycle with the cell cycle, thus ensuring bipolar mitotic spindle fidelity. Understanding this process will help to delineate the relationship between centrosomal abnormalities and spindle defects.

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Protein phosphatase 6 regulates mitotic spindle formation by controlling the T-loop phosphorylation state of Aurora A bound to its activator TPX2

Abstract: Loss of PP6 function interferes with spindle formation and chromosome alignment because of amplified Aurora A activity.

Cited by 170 publications

References 66 publications

Melanoma-associated mutations in protein phosphatase 6 cause chromosome instability and DNA damage due to dysregulated Aurora-A

Melanoma-associated mutations in protein phosphatase 6 cause chromosome instability and DNA damage due to dysregulated Aurora-A

Activation of Aurora-A Kinase by Protein Partner Binding and Phosphorylation Are Independent and Synergistic

The role of mitotic kinases in coupling the centrosome cycle with the assembly of the mitotic spindle

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