Usp16 regulates kinetochore localization of Plk1 to promote proper chromosome alignment in mitosis

Zhuo, Xiaolong; Guo, Xiao; Zhang, Xiaoyan; Jing, Guihua; Wang, Yao; Chen, Qiang; Jiang, Qing; Liu, Junjun; Zhang, Chuanmao

doi:10.1083/jcb.201502044

Cited by 44 publications

(34 citation statements)

References 30 publications

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“…Recently, CDK1 dependent phosphorylation of Usp16 on S552 was shown to promote an interaction between Usp16 and Plk1. This interaction results in deubiquitination of Plk1 and sustained kinetochore localization of Plk1 during metaphase that is necessary for initial kinetochore-microtubule attachment, proper chromosome alignment, and timely chromatid segregation [82]. In addition, TTK has been found to cooperate with Plk1 to regulate the SAC through phosphorylation of KNL-1 [83].…”

Section: Discussionmentioning

confidence: 99%

Genetic and pharmacological inhibition of TTK impairs pancreatic cancer cell line growth by inducing lethal chromosomal instability

et al. 2017

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Pancreatic ductal adenocarcinoma, which accounts for the majority of pancreatic cancers, is a lethal disease with few therapeutic options. Genomic profiling of pancreatic ductal adenocarcinoma has identified a complex and heterogeneous landscape. Understanding the molecular characteristics of pancreatic ductal adenocarcinoma will facilitate the identification of potential therapeutic strategies. We analyzed the gene expression profiles of primary tumors from patients compared to normal pancreas and identified high co-overexpression of core components of the spindle assembly checkpoint, including the protein kinase TTK (also known as MPS-1). We found overexpression of TTK protein in a subset of pancreatic ductal adenocarcinoma primary tumors and cell lines. siRNA-mediated depletion or catalytic inhibition of TTK resulted in an aberrant cell cycle profile, multi- and micro-nucleation, induction of apoptosis, and decreased cell proliferation and transformed growth. Selective catalytic inhibition of TTK caused override of the spindle assembly checkpoint-induced cell cycle arrest. Interestingly, we identified ubiquitin specific peptidase 16 (Usp16), an ubiquitin hydrolase, as a phosphorylation substrate of TTK. Usp16 regulates chromosomal condensation and G2/M progression by deubiquitinating histone H2A and polo-like kinase 1. Phosphomimetic mutants of Usp16 show enhanced proteosomal degradation and may prolong the G2/M transition allowing for correction of replication errors. Taken together, our results suggest a critical role for TTK in preventing aneuploidy-induced cell death in pancreatic cancer.

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Section: Discussionmentioning

confidence: 99%

Genetic and pharmacological inhibition of TTK impairs pancreatic cancer cell line growth by inducing lethal chromosomal instability

et al. 2017

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“…Thus, the function of USP16 in other signaling pathways, particularly in calcium-insensitive cell types, needs to be further investigated. Third, current evidence indicates that USP16 phosphorylation mediated by some mitosis-related kinases, such as Aurora B or PLK1, enhances its DUB activity (23,55). However, the expression levels of Aurora B and PLK1 were undetectable at the early stages of T cell activation (56).…”

Section: Methodsmentioning

confidence: 97%

“…USP16 is a deubiquitinase (DUB) that has been found to be required for chromosomal segregation in mitosis (23). USP16 promotes the localization and maintenance of polo-like kinase 1 (PLK1) on kinetochores, which are important for proper chromosome alignment.…”

Section: Introductionmentioning

confidence: 99%

USP16-mediated deubiquitination of calcineurin A controls peripheral T cell maintenance

Zhang¹,

Liu²,

Cao³

et al. 2019

Journal of Clinical Investigation

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“…As discussed earlier, this helps to enhance SAC signaling by allowing Plk1 to co-operate with Mps1 to phosphorylate the Knl1-MELT motifs (Espeut et al, 2015 ; Von Schubert et al, 2015 ; Ikeda and Tanaka, 2017 ) (arrow 19). Finally, there are also at least two other ways that Cdk1 can influence Plk1 activity at kinetochores: (1) Cdk1 primes USP16 for phosphorylation and activation by Plk1, which establishes a positive feedback loop that helps to maintain Plk1 on kinetochores by antagonizing its CUL3–KLHL22-mediated ubiquitylation and removal (Beck et al, 2013 ; Zhuo et al, 2015 ), (2) Cdk1 phosphorylates the MYPT1-PP1 complex to enhance Plk1 interaction and decrease Plk1 activity (Yamashiro et al, 2008 ; Dumitru et al, 2017 ). Although these connections can both impact on kinetochore-localized Plk1 activity, they are not currently annotated on Figure 2A because it is still unclear whether this regulation occurs locally at the KMN network.…”

Section: The Role Of Cdk1 In Regulating Kinetochore-microtubule Attacmentioning

confidence: 99%

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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Usp16 regulates kinetochore localization of Plk1 to promote proper chromosome alignment in mitosis

Abstract: CDK1 and Plk1 sequentially phosphorylate and activate Usp16, which in turn deubiquitinates Plk1 to maintain the kinase’s kinetochore localization and promote proper chromosome alignment in mitosis.

Cited by 44 publications

References 30 publications

Genetic and pharmacological inhibition of TTK impairs pancreatic cancer cell line growth by inducing lethal chromosomal instability

Genetic and pharmacological inhibition of TTK impairs pancreatic cancer cell line growth by inducing lethal chromosomal instability

USP16-mediated deubiquitination of calcineurin A controls peripheral T cell maintenance

Kinase and Phosphatase Cross-Talk at the Kinetochore

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