CDK1-CCNB1 creates a spindle checkpoint–permissive state by enabling MPS1 kinetochore localization

Hayward, Daniel; Alfonso-Pérez, Tatiana; Cundell, Michael J.; Hopkins, M. J. G.; Holder, James; Bancroft, James; Hutter, Lukas; Novák, Béla; Barr, Francis A.; Grüneberg, Ulrike

doi:10.1083/jcb.201808014

Cited by 49 publications

(96 citation statements)

References 86 publications

(139 reference statements)

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“…Specific enrichment of Cdk1 kinase activity at a particular cellular localisation could also be important. Accordingly, cyclin B is known to be recruited to the kinetochore and has recently been shown to contribute to spindle assembly checkpoint signalling by phosphorylating Mps1 . A large subset of the cyclin B‐specific substrates that we have identified using degron‐mediated depletion is indeed associated with the centromere/kinetochore, supporting the importance of this targeted localisation of cyclin B .…”

Section: Pulling the Trigger: Cdk1 Activationsupporting

confidence: 63%

Triggering mitosis

Crncec

Hochegger

2019

FEBS Letters

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Entry into mitosis is triggered by the activation of cyclin‐dependent kinase 1 (Cdk1). This simple reaction rapidly and irreversibly sets the cell up for division. Even though the core step in triggering mitosis is so simple, the regulation of this cellular switch is highly complex, involving a large number of interconnected signalling cascades. We do have a detailed knowledge of most of the components of this network, but only a poor understanding of how they work together to create a precise and robust system that ensures that mitosis is triggered at the right time and in an orderly fashion. In this review, we will give an overview of the literature that describes the Cdk1 activation network and then address questions relating to the systems biology of this switch. How is the timing of the trigger controlled? How is mitosis insulated from interphase? What determines the sequence of events, following the initial trigger of Cdk1 activation? Which elements ensure robustness in the timing and execution of the switch? How has this system been adapted to the high levels of replication stress in cancer cells?

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Section: Pulling the Trigger: Cdk1 Activationsupporting

confidence: 63%

Triggering mitosis

Crncec

Hochegger

2019

FEBS Letters

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“…MPS1 has an N‐terminal kinetochore binding domain which associates with the NDC80/NUF2 complex at the kinetochore . It has now been shown that the N‐terminal Ser281 within the kinetochore binding domain of MPS1 has to be phosphorylated to allow efficient kinetochore recruitment of MPS1 . These data are consistent with biochemical data showing an improved binding of Ser281‐phosphorylated MPS1 to purified NDC80 complex .…”

Section: Molecular Targets Of Cdk1‐cyclin B1supporting

confidence: 81%

“…The presence or absence of CDK1 activity affects the kinetochore recruitment of all core SAC proteins implying that one or more upstream components of the SAC are regulated by CDK1 [97]. In line with this idea, it has been suggested that both localization and [169,170] activation of MPS1 are controlled by CDK1-cyclin B1 [45,98,99]. It has recently been demonstrated that phosphorylation of MPS1 by CDK1-cyclin B1 controls recruitment of MPS1 to the kinetochore in human cells [45].…”

Section: Molecular Targets Of Cdk1-cyclin B1mentioning

confidence: 94%

“…Experimental measurements of the minimal cellular level of cyclin B1 required to support a SAC response indicated that the threshold for effective SAC signalling is located at ~ 75 n m cyclin B1 (Fig. ) . This relationship allows the SAC to be responsive until the point of chromosome segregation.…”

Section: Relationship Between Cyclin B1 Levels and Pp2a‐b55 Activatiomentioning

confidence: 99%

“…Their specific mode of inhibition, characterized by high binding affinity to PP2A‐B55 and very slow dephosphorylation kinetics, has been termed ‘unfair inhibition’ . The MASTL kinase is activated by CDK1 phosphorylation of its activation loop, and PP2A‐B55 activity is hence indirectly determined by the level of cyclin B1 and active CDK1‐cyclin B1 complex .…”

Section: Regulation Of Pp2a‐b55 Activity By the Mastl‐ensa Systemmentioning

confidence: 99%

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Orchestration of the spindle assembly checkpoint by CDK1‐cyclin B1

2019

Self Cite

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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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From the Nuclear Pore to the Fibrous Corona: A MAD Journey to Preserve Genome Stability

Cunha-Silva

Conde

2020

BioEssays

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The relationship between kinetochores and nuclear pore complexes (NPCs) is intimate but poorly understood. Several NPC components and associated proteins are relocated to mitotic kinetochores to assist in different activities that ensure faithful chromosome segregation. Such is the case of the Mad1-c-Mad2 complex, the catalytic core of the spindle assembly checkpoint (SAC), a surveillance pathway that delays anaphase until all kinetochores are attached to spindle microtubules. Mad1-c-Mad2 is recruited to discrete domains of unattached kinetochores from where it promotes the rate-limiting step in the assembly of anaphase-inhibitory complexes. SAC proficiency further requires Mad1-c-Mad2 to be anchored at NPCs during interphase. However, the mechanistic relevance of this arrangement for SAC function remains ill-defined. Recent studies uncover the molecular underpinnings that coordinate the release of Mad1-c-Mad2 from NPCs with its prompt recruitment to kinetochores. Here, current knowledge on Mad1-c-Mad2 function and spatiotemporal regulation is reviewed and the critical questions that remain unanswered are highlighted.

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CDK1-CCNB1 creates a spindle checkpoint–permissive state by enabling MPS1 kinetochore localization

Cited by 49 publications

References 86 publications

Triggering mitosis

Triggering mitosis

Orchestration of the spindle assembly checkpoint by CDK1‐cyclin B1

From the Nuclear Pore to the Fibrous Corona: A MAD Journey to Preserve Genome Stability

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