Acetylation of Aurora B by TIP60 ensures accurate chromosomal segregation

Mo, Fei; Zhuang, Xiaoxuan; Liu, Xing; Yao, Phil; Qin, Bo; Su, Zeqi; Zang, Jianye; Wang, Zhiyong; Zhang, Jiancun; Dou, Zhen; Tian, Changlin; Teng, Maikun; Niu, Liwen; Hill, Donald L.; Fang, Guowei; Ding, Xia; Fu, Chuanhai; Yao, Xuebiao

doi:10.1038/nchembio.2017

Cited by 88 publications

(107 citation statements)

References 50 publications

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“…1F, FLAG-Sds22 proteins were immunoisolated from DMSO-and BI 2536-treated HeLa cells. Sds22 protein bands, from DMSO-and BI 2536-treated cells, were removed for ingel digestion followed by mass spectrometric identification (12 Phosphorylation of Sds22 Is Critical for Accurate Mitotic Progression-To examine the role of PLK1-mediated phosphorylation of Sds22 in mitosis, we generated non-phosphorylatable and phosphomimetic Sds22 mutants tagged with GFP, which were transiently transfected into HeLa cells together with mCherry-H2B. Comparison of expression levels of exogenous and endogenous Sds22 were shown in Fig.…”

Section: Plk1 Interacts With and Phosphorylatesmentioning

confidence: 99%

“…During mitotic spindle assembly, centromere-localized Aurora B destabilizes kinetochore-microtubule interactions that are under low mechanical tension (2,9) by phosphorylating several components of the outer kinetochore, including NDC80/Hec1, KNL-1, and Dsn1 (3,10). The Aurora B-mediated error correction is important for bipolar attachment of all chromosomes, which satisfies the SAC to initiate anaphase (11,12).…”

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confidence: 99%

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Phosphorylation of PP1 Regulator Sds22 by PLK1 Ensures Accurate Chromosome Segregation

Duan

Wang²,

Wang

et al. 2016

Journal of Biological Chemistry

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During cell division, accurate chromosome segregation is tightly regulated by Polo-like kinase 1 (PLK1) and opposing activities of Aurora B kinase and protein phosphatase 1 (PP1). However, the regulatory mechanisms underlying the aforementioned hierarchical signaling cascade during mitotic chromosome segregation have remained elusive. Sds22 is a conserved regulator of PP1 activity, but how it regulates PP1 activity in space and time during mitosis remains elusive. Here we show that Sds22 is a novel and cognate substrate of PLK1 in mitosis, and the phosphorylation of Sds22 by PLK1 elicited an inhibition of PP1-mediated dephosphorylation of Aurora B at threonine 232 (Thr 232 ) in a dose-dependent manner. Overexpression of a phosphomimetic mutant of Sds22 causes a dramatic increase in mitotic delay, whereas overexpression of a non-phosphorylatable mutant of Sds22 results in mitotic arrest. Mechanistically, the phosphorylation of Sds22 by PLK1 strengthens the binding of Sds22 to PP1 and inhibits the dephosphorylation of Thr 232 of Aurora B to ensure a robust, error-free metaphase-anaphase transition. These findings delineate a conserved signaling hierarchy that orchestrates dynamic protein phosphorylation and dephosphorylation of critical mitotic regulators during chromosome segregation to guard chromosome stability.

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Section: Plk1 Interacts With and Phosphorylatesmentioning

confidence: 99%

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confidence: 99%

Phosphorylation of PP1 Regulator Sds22 by PLK1 Ensures Accurate Chromosome Segregation

Duan

Wang²,

Wang

et al. 2016

Journal of Biological Chemistry

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“…DNA was stained with DAPI (Sigma). Images were acquired with a DeltaVision wide-field deconvolution microscope (Applied Precision Inc.) as described previously (44). For single cell migration, MDA-MB-231 cells were cultured in a glass-bottom culture dish (MatTek).…”

Section: Methodsmentioning

confidence: 99%

The Microtubule Plus End Tracking Protein TIP150 Interacts with Cortactin to Steer Directional Cell Migration

Adams

Zhang

Wang

et al. 2016

Journal of Biological Chemistry

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Cell migration is orchestrated by dynamic interactions of microtubules with the plasma membrane cortex. How these interactions facilitate these dynamic processes is still being actively investigated. TIP150 is a newly characterized microtubule plus end tracking protein essential for mitosis and entosis (Ward, T., Wang, M., Liu, X., Wang, Z., Xia, P., Chu, Y., Wang, X., Liu, L., Jiang, K., Yu, H., Yan, M., Wang, J., Hill, D. L., Huang, Y., Zhu, T., and Yao, X. (2013) Regulation of a dynamic interaction between two microtubule-binding proteins, EB1 and TIP150, by the mitotic p300/CBP-associated factor (PCAF) orchestrates kinetochore microtubule plasticity and chromosome stability during mitosis. J. Biol. Chem. 288, 15771-15785; Xia, P., Zhou, J., Song, X., Wu, B., Liu, X., Li, D., Zhang, S., Wang, Z., Yu, H., Ward, T., Zhang, J., Li, Y., Wang, X., Chen, Y., Guo, Z., and Yao, X. (2014) Aurora A orchestrates entosis by regulating a dynamic MCAK-TIP150 interaction. J. Mol. Cell Biol. 6, 240 -254). Here we show that TIP150 links dynamic microtubules to steer cell migration by interacting with cortactin. Mechanistically, TIP150 binds to cortactin via its C-terminal tail. Interestingly, the C-terminal TIP150 proline-rich region (CT150) binds to the Src homology 3 domain of cortactin specifically, and such an interaction is negatively regulated by EGF-elicited tyrosine phosphorylation of cortactin. Importantly, suppression of TIP150 or overexpression of phospho-mimicking cortactin inhibits polarized cell migration. In addition, CT150 disrupts the biochemical interaction between TIP150 and cortactin in vitro, and perturbation of the TIP150-cortactin interaction in vivo using a membrane-permeable TAT-CT150 peptide results in an inhibition of directional cell migration. We reason that a dynamic TIP150-cortactin interaction orchestrates directional cell migration via coupling dynamic microtubule plus ends to the cortical cytoskeleton.Cell migration is an essential physiological function that is tightly regulated in numerous biological processes, including development, tissue remodeling, wound healing, and tumor metastasis (1, 2). These processes require coordination of dynamic reorganization between the actin filaments and microtubules.Cortactin (CTN) 6 is a multidomain-containing scaffold protein that consists of an N-terminal acidic domain, six and a half tandem repeats, an ␣ helix, a proline-rich region, and an Src Homology (SH3) domain at its C terminus (3). CTN is an important scaffold for promoting the polymerization and rearrangement of the actin cytoskeleton (4). Functionally, CTN, distributed at protrusions and the leading edges, is necessary for cell migration by regulating intercellular adhesion and cell spreading (5). Importantly, CTN is phosphorylated at tyrosine residues in response to growth factor receptors, which regulates cell migration (6).Microtubules, one of the three major components of the cytoskeleton, are required for maintaining the physical and plastic properties of migrating cells (7). The plus en...

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“…The critical role of K134 Ran in binding to Mog1 prompted us to conduct computational analyses for lysine acetylation (Li et al, 2006), which suggested K134 Ran as a potential substrate of TIP60 (Mo et al, 2016). Given our recent demonstration that TIP60-dependent acetylation is critical for accurate chromosome segregation in mitosis (Mo et al, 2016), we postulated that TIP60 may acetylate K134 Ran to retain a dynamic Ran–Mog1 interaction for accurate kinetochore-microtubule interactions in mitosis. Specifically, our structural analyses suggest that persistent acetylation of K134 Ran would disrupt the Ran–Mog1 interaction.…”

Section: Resultsmentioning

confidence: 99%

“…Our findings provide structural delineation of molecular mechanism by which post-translational modifications could yield sharp transitions between functionally distinct Ran-GTPase states, generating nonlinearity in Ran signaling cascades, and contributing to the spindle plasticity control during cell division cycle. It is worth noting that TIP60 localization depends on Ndc80 (Mo et al, 2016), and TIP60-elicited acetylation of Ran would provide centromere-based spatial control of Ran-GTP gradient centered on kinetochore (Figure 6G). Thus, our study points to an intricate cross-talk among Cdk1, TIP60, Ndc80, and Ran-GTPase in sensing kinetochore-microtubule attachment.…”

Section: Discussionmentioning

confidence: 99%

Mitosis-specific acetylation tunes Ran effector binding for chromosome segregation

Bao

Liu

et al. 2017

Journal of Molecular Cell Biology

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Stable transmission of genetic information during cell division requires faithful mitotic spindle assembly and chromosome segregation. The Ran GTPase plays a key role in mitotic spindle assembly. However, how the generation of a chemical gradient of Ran-GTP at the spindle is coupled to mitotic post-translational modifications has never been characterized. Here, we solved the complex structure of Ran with the nucleotide release factor Mog1 and delineated a novel mitosis-specific acetylation-regulated Ran–Mog1 interaction during chromosome segregation. Our structure-guided functional analyses revealed that Mog1 competes with RCC1 for Ran binding in a GTP/GDP-dependent manner. Biochemical characterization demonstrated that Mog1-bound Ran prevents RCC1 binding and subsequent GTP loading. Surprisingly, Ran is a bona fide substrate of TIP60, and the acetylation of Lys134 by TIP60 liberates Mog1 from Ran binding during mitosis. Importantly, this acetylation-elicited switch of Ran binding to RCC1 promotes high level of Ran-GTP, which is essential for chromosome alignment. These results establish a previously uncharacterized regulatory mechanism in which TIP60 provides a homeostatic control of Ran-GTP level by tuning Ran effector binding for chromosome segregation in mitosis.

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Acetylation of Aurora B by TIP60 ensures accurate chromosomal segregation

Cited by 88 publications

References 50 publications

Phosphorylation of PP1 Regulator Sds22 by PLK1 Ensures Accurate Chromosome Segregation

Phosphorylation of PP1 Regulator Sds22 by PLK1 Ensures Accurate Chromosome Segregation

The Microtubule Plus End Tracking Protein TIP150 Interacts with Cortactin to Steer Directional Cell Migration

Mitosis-specific acetylation tunes Ran effector binding for chromosome segregation

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