Regulated targeting of protein phosphatase 1 to the outer kinetochore by KNL1 opposes Aurora B kinase

Lens

Journal of Cell Science

2011

243

354

SummaryPrecise control of the attachment strength between kinetochores and spindle microtubules is essential to preserve genomic stability. Aurora B kinase has been implicated in regulating the stability of kinetochore-microtubule attachments but its relevant kinetochore targets in cells remain unclear. Here, we identify multiple serine residues within the N-terminus of the kinetochore protein Hec1 that are phosphorylated in an Aurora-B-kinase-dependent manner during mitosis. On all identified target sites, Hec1 phosphorylation at kinetochores is high in early mitosis and decreases significantly as chromosomes bi-orient. Furthermore, once dephosphorylated, Hec1 is not highly rephosphorylated in response to loss of kinetochore-microtubule attachment or tension. We find that a subpopulation of Aurora B kinase remains localized at the outer kinetochore even upon Hec1 dephosphorylation, suggesting that Hec1 phosphorylation by Aurora B might not be regulated wholly by spatial positioning of the kinase. Our results define a role for Hec1 phosphorylation in kinetochore-microtubule destabilization and error correction in early mitosis and for Hec1 dephosphorylation in maintaining stable attachments in late mitosis.

Section: Hec1 Dephosphorylation By Protein Phosphatasecontrasting

confidence: 47%

Section: Discussionmentioning

confidence: 99%

Temporal changes in Hec1 phosphorylation control kinetochore–microtubule attachment stability during mitosis

Lens

Journal of Cell Science

2011

243

354

“…This sets up a gradient of phosphorylation activity between the centromere and the kinetochore. This is sharpened by a feedback loop between Aurora B and PP1 because Aurora B phosphorylates PP1 and prevents its binding to KNL1 [65,66]. As a result, the closer the kinetochore is to the centromere, the higher the effective activity of Aurora B.…”

Section: Local Decisions At Kinetochores: Error Correctionmentioning

confidence: 99%

“…Aurora B activity is further spatially restricted because INCENP has to be phosphorylated on its C-terminus in trans by other Aurora B kinases [59]; therefore, with another nod to Turing, Aurora B only gains full activity when CPCs are clustered. Opposing Aurora B is the PP1g phosphatase that is recruited to the outer kinetochore by the kinetochore-null 1 (KNL1) protein [65]. This sets up a gradient of phosphorylation activity between the centromere and the kinetochore.…”

Section: Local Decisions At Kinetochores: Error Correctionmentioning

confidence: 99%

The Renaissance or the cuckoo clock

Pines

Hagan

2011

Phil. Trans. R. Soc. B

‘…in Italy, for thirty years under the Borgias, they had warfare, terror, murder and bloodshed, but they produced Michelangelo, Leonardo da Vinci and the Renaissance. In Switzerland, they had brotherly love, they had five hundred years of democracy and peace—and what did that produce? The cuckoo clock’. Orson Welles as Harry Lime : The Third Man Orson Welles might have been a little unfair on the Swiss, after all cuckoo clocks were developed in the Schwartzwald, but, more importantly, Swiss democracy gives remarkably stable government with considerable decision-making at the local level. The alternative is the battling city-states of Renaissance Italy: culturally rich but chaotic at a higher level of organization. As our understanding of the cell cycle improves, it appears that the cell is organized more along the lines of Switzerland than Renaissance Italy, and one major challenge is to determine how local decisions are made and coordinated to produce the robust cell cycle mechanisms that we observe in the cell as a whole.

Methods in Molecular Biology

“…Finally, BUB1 promotes Aurora B localization by phosphorylating histone H2A on T120. Therefore the error-correction and SAC pathways are extensively entwined, and this is further exemplified by the fact that the phosphatases PP1 and PP2A-B56 counteract both error-correction and the SAC to stabilize chromosome spindle attachments and allow anaphase onset (9)(10)(11)(12)(13)(14).…”

Section: )mentioning

confidence: 99%

Studying Kinetochore Kinases

Saurin

Kops

2016

Mitotic kinetochores are signaling network hubs that regulate chromosome movements, attachment error-correction, and the spindle assembly checkpoint. Key switches in these networks are kinases and phosphatases that enable rapid responses to changing conditions. Describing the mechanisms and dynamics of their localized activation and deactivation is therefore instrumental for understanding the spatio-temporal control of chromosome segregation.