Spindle assembly checkpoint robustness requires Tpr-mediated regulation of Mad1/Mad2 proteostasis

Schweizer, Nina; Ferrás, Cristina; Kern, David; Logarinho, Elsa; Cheeseman, Iain M.; Maiato, Hélder

doi:10.1083/jcb.201309076

Cited by 66 publications

(90 citation statements)

References 41 publications

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“…We imaged transiently transfected GFP-positive live cells through mitosis, from the appearance of the metaphase plate until the end of anaphase. In accordance with the findings of Schweizer et al (Schweizer et al, 2013), the transition time from metaphase to anaphase was shortened in Tpr-depleted cells (Fig. 8A,B).…”

Section: Phosphorylation Of Tpr Is Crucial For Mediating Its Role In supporting

confidence: 93%

“…Recently, Tpr-depleted cells were shown to undergo accelerated mitosis, and Tpr-mediated stabilization of Mad1 and Mad2 was shown to be required for a normal spindle assembly checkpoint response (Schweizer et al, 2013). As the data presented in Fig.…”

Section: Phosphorylation Of Tpr Is Crucial For Mediating Its Role In mentioning

confidence: 87%

“…The nucleoporin Tpr has been shown to be crucial for the maintenance of SAC proteostasis in all stages of the cell cycle. Tpr is essential for the localization of Mad2 but not Mad1 to the kinetochores (Schweizer et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Depletion of Tpr also results in enhanced p53 accumulation in the cell nucleus, resulting in a senescence-like phenotype and facilitating autophagy (DavidWatine, 2011;Funasaka et al, 2012). Recently, Tpr was shown to be required for maintaining the homeostasis of Mad proteins and for the normal spindle assembly checkpoint response (Schweizer et al, 2013). We undertook the present study with the aim of investigating the phosphorylation status of the Tpr protein and the significance of specific Tpr phosphorylation events during cell cycle progression.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Phosphorylation of nucleoporin Tpr governs its differential localization and is required for its mitotic function

Rajanala

Sarkar

Jhingan

et al. 2014

Journal of Cell Science

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A major constituent of the nuclear basket region of the nuclear pore complex (NPC), nucleoporin Tpr, plays roles in regulating multiple important processes. We have previously established that Tpr is phosphorylated in both a MAP-kinase-dependent and MAP-kinaseindependent manner, and that Tpr acts as both a substrate and as a scaffold for ERK2 (also known as MAPK1). Here, we report the identification of S2059 and S2094 as the major novel ERKindependent phosphorylation sites and T1677, S2020, S2023 and S2034 as additional ERK-independent phosphorylation sites found in the Tpr protein in vivo. Our results suggest that protein kinase A phosphorylates the S2094 residue and that the site is hyperphosphorylated during mitosis. Furthermore, we find that Tpr is phosphorylated at the S2059 residue by CDK1 and the phosphorylated form distinctly localizes with chromatin during telophase. Abrogation of S2059 phosphorylation abolishes the interaction of Tpr with Mad1, thus compromising the localization of both Mad1 and Mad2 proteins, resulting in cell cycle defects. The identification of novel phosphorylation sites on Tpr and the observations presented in this study allow better understanding of Tpr functions.

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Section: Phosphorylation Of Tpr Is Crucial For Mediating Its Role In supporting

confidence: 93%

Section: Phosphorylation Of Tpr Is Crucial For Mediating Its Role In mentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Phosphorylation of nucleoporin Tpr governs its differential localization and is required for its mitotic function

Rajanala

Sarkar

Jhingan

et al. 2014

Journal of Cell Science

View full text Add to dashboard Cite

show abstract

“…It has been shown that the amino-terminal half of Mad1 contains a nuclear pore binding site. 49,50 Several functions are reported for Mad1 localizing at the nuclear pore: pre-mitotic anaphase inhibitor formation, 49 Mad1-Mad2 proteostasis, 51 and the regulation of nuclear-cytoplasmic transport. 52 Most recently, the kinesin-binding motif was mapped at the very end of the amino-terminus, which associates directly with Cut7/kinesin-5 in fission yeast and with CENP-E/kinesin-7 in human cells 21 (Fig.…”

Section: Identification Of a Conserved Motif In Mad1 For Kinesin Bindingmentioning

confidence: 99%

The spindle assembly checkpoint promotes chromosome bi-orientation: A novel Mad1 role in chromosome alignment

Akera

Watanabe

2016

Cell Cycle

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Faithful chromosome segregation relies on dynamic interactions between spindle microtubules and chromosomes. Especially, all chromosomes must be aligned at the equator of the spindle to establish biorientation before they start to segregate. The spindle assembly checkpoint (SAC) monitors this process, inhibiting chromosome segregation until all chromosomes achieve bi-orientation. The original concept of 'checkpoints' was proposed as an external surveillance system that does not play an active role in the process it monitors. However, accumulating evidence from recent studies suggests that SAC components do play an active role in chromosome bi-orientation. In this review, we highlight a novel Mad1 role in chromosome alignment, which is the first conserved mechanism that links the SAC and kinesin-mediated chromosome gliding.

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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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Spindle assembly checkpoint robustness requires Tpr-mediated regulation of Mad1/Mad2 proteostasis

Abstract: Tpr is a kinetochore-independent, rate-limiting factor required to mount and sustain a robust spindle assembly checkpoint response by stabilizing Mad1 and Mad2 before mitosis.

Cited by 66 publications

References 41 publications

Phosphorylation of nucleoporin Tpr governs its differential localization and is required for its mitotic function

Phosphorylation of nucleoporin Tpr governs its differential localization and is required for its mitotic function

The spindle assembly checkpoint promotes chromosome bi-orientation: A novel Mad1 role in chromosome alignment

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

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