A Kinase-Phosphatase Network that Regulates Kinetochore-Microtubule Attachments and the SAC

Vallardi, Giulia; Cordeiro, Marília H.; Saurin, Adrian T.

doi:10.1007/978-3-319-58592-5_19

Cited by 19 publications

(14 citation statements)

References 197 publications

(300 reference statements)

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“…Many theories have been put forward to explain tension-sensing, including inter/intra-kinetochore distance changes and structural changes within the kinetochore itself, but most of these models focus on the ability of tension to restrict Aurora B from accessing its outer kinetochore substrates. However, as pointed out recently by others (Lampson and Grishchuk, 2017 ), tension may also impact directly on local phosphatase activity (Vallardi et al, 2017 ). In fact, it may be difficult to discriminate between these two possibilities because Aurora B exhibits bistable activity in the presence of a phosphatase (Zaytsev et al, 2016 ); therefore, phosphatase activation may switch-off Aurora B activity.…”

Section: Discussionmentioning

confidence: 78%

“…It is perhaps not surprising, therefore, that at a molecular level these processes are extremely well connected. In fact, they are each regulated by an overlapping network of enzymes that includes at least five kinases (Aurora B, Mps1, Bub1, Plk1, and Cdk1) and two phosphatases (PP1 and PP2A-B56) (Funabiki and Wynne, 2013 ; Vallardi et al, 2017 ). Although these enzymes undoubtedly have very specific roles at the kinetochore, sometimes in only one particular process, their multiple interconnections mean that it is incredibly difficult to dissociate their direct from indirect effects.…”

Section: Introductionmentioning

confidence: 99%

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Kinase and Phosphatase Cross-Talk at the Kinetochore

Saurin

2018

Front. Cell Dev. Biol.

122

137

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Multiple kinases and phosphatases act on the kinetochore to control chromosome segregation: Aurora B, Mps1, Bub1, Plk1, Cdk1, PP1, and PP2A-B56, have all been shown to regulate both kinetochore-microtubule attachments and the spindle assembly checkpoint. Given that so many kinases and phosphatases converge onto two key mitotic processes, it is perhaps not surprising to learn that they are, quite literally, entangled in cross-talk. Inhibition of any one of these enzymes produces secondary effects on all the others, which results in a complicated picture that is very difficult to interpret. This review aims to clarify this picture by first collating the direct effects of each enzyme into one overarching schematic of regulation at the Knl1/Mis12/Ndc80 (KMN) network (a major signaling hub at the outer kinetochore). This schematic will then be used to discuss the implications of the cross-talk that connects these enzymes; both in terms of why it may be needed to produce the right type of kinetochore signals and why it nevertheless complicates our interpretations about which enzymes control what processes. Finally, some general experimental approaches will be discussed that could help to characterize kinetochore signaling by dissociating the direct from indirect effect of kinase or phosphatase inhibition in vivo. Together, this review should provide a framework to help understand how a network of kinases and phosphatases cooperate to regulate two key mitotic processes.

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Section: Discussionmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Kinase and Phosphatase Cross-Talk at the Kinetochore

Saurin

2018

Front. Cell Dev. Biol.

122

137

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“…Only end-on attachments can impart pulling forces to segregate chromosomes apart and in the absence of end-on attachments, checkpoint proteins are retained at the kinetochore which prevents premature chromosome segregation (reviewed in Musacchio and Desai, 2017; Cheeseman, 2014). A highly responsive set of kinases and phosphatases together monitor and signal kinetochore-microtubule (KT-MT) attachment status (reviewed in Saurin and Kops, 2016; Vallardi et al, 2017). Whether a similar highly responsive kinase-phosphatase feedback loop exists to selectively and rapidly stabilise end-on attachments is not known; this is important to establish as rapid stabilisation of end-on attachments is essential for withstanding microtubule-end mediated pulling forces that may otherwise detach kinetochore-microtubule attachments as soon as they form.…”

Section: Introductionmentioning

confidence: 99%

Kinetochores attached to microtubule-ends are stabilised by Astrin bound PP1 to ensure proper chromosome segregation

Conti

Gul

Islam

et al. 2019

eLife

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Microtubules segregate chromosomes by attaching to macromolecular kinetochores. Only microtubule-end attached kinetochores can be pulled apart; how these end-on attachments are selectively recognised and stabilised is not known. Using the kinetochore and microtubule-associated protein, Astrin, as a molecular probe, we show that end-on attachments are rapidly stabilised by spatially-restricted delivery of PP1 near the C-terminus of Ndc80, a core kinetochore-microtubule linker. PP1 is delivered by the evolutionarily conserved tail of Astrin and this promotes Astrin’s own enrichment creating a highly-responsive positive feedback, independent of biorientation. Abrogating Astrin:PP1-delivery disrupts attachment stability, which is not rescued by inhibiting Aurora-B, an attachment destabiliser, but is reversed by artificially tethering PP1 near the C-terminus of Ndc80. Constitutive Astrin:PP1-delivery disrupts chromosome congression and segregation, revealing a dynamic mechanism for stabilising attachments. Thus, Astrin-PP1 mediates a dynamic ‘lock’ that selectively and rapidly stabilises end-on attachments, independent of biorientation, and ensures proper chromosome segregation.

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“…This provides the unattached KT an opportunity to attach to a MT from the correct spindle pole [1,3,4]. Together, these observations suggest that a balance between kinase and phosphatase activities is required to break erroneous attachments and then establish correct, stable attachments between KTs and MTs [12][13][14]. Experiments show that a PP1 phosphatase (Glc7 is the PP1 catalytic subunit in budding yeast) opposes the kinase activity of Ipl1 [15][16][17], but whether it dephosphorylates Ndc80 or not and its importance in biorientation of chromosomes remain unclear.…”

Section: Introductionmentioning

confidence: 93%

A stochastic model for error correction of kinetochore-microtubule attachments in budding yeast

et al. 2020

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To divide replicated chromosomes equally between daughter cells, kinetochores must attach to microtubules emanating from opposite poles of the mitotic spindle (biorientation). An error correction mechanism facilitates this process by destabilizing erroneous kinetochore-microtubule attachments. Here we present a stochastic model of kinetochore-microtubule attachments, via an essential protein Ndc80 in budding yeast, Saccharomyces cerevisiae. Using the model, we calculate the stochastic dynamics of a pair of sister kinetochores as they transition among different attachment states. First of all, we determine the kinase-to-phosphatase balance point that maximizes the probability of biorientation, while starting from an erroneous attachment state. We find that the balance point is sensitive to the rates of microtubule-Ndc80 dissociation and derive an approximate analytical formula that defines the balance point. Secondly, we determine the probability of transition from lowtension amphitelic to monotelic attachment and find that, despite this probability being approximately 33%, biorientation can be achieved with high probability. Thirdly, we calculate the contribution of the geometrical orientation of sister kinetochores to the probability of biorientation and show that, in the absence of geometrical orientation, the biorientation error rate is much larger than that observed in experiments. Finally, we study the coupling of the error correction mechanism to the spindle assembly checkpoint by calculating the average binding of checkpoint-related proteins to the kinetochore during the error correction process.

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A Kinase-Phosphatase Network that Regulates Kinetochore-Microtubule Attachments and the SAC

Cited by 19 publications

References 197 publications

Kinase and Phosphatase Cross-Talk at the Kinetochore

Kinase and Phosphatase Cross-Talk at the Kinetochore

Kinetochores attached to microtubule-ends are stabilised by Astrin bound PP1 to ensure proper chromosome segregation

A stochastic model for error correction of kinetochore-microtubule attachments in budding yeast

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