KNL1 facilitates phosphorylation of outer kinetochore proteins by promoting Aurora B kinase activity

Caldas, Gina V.; DeLuca, Keith F.; DeLuca, Jennifer G.

doi:10.1083/jcb.201306054

Cited by 70 publications

(92 citation statements)

References 46 publications

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“…One possibility is that it influences the activity or accessibility of the kinetochore protein Knl1, which, when phosphorylated by Mps1, has been shown to be a docking site for Bub3 and Bub1 kinase and a factor in Aurora B kinase localization and activity (Shepperd et al, 2012;Yamagishi et al, 2012;Caldas et al, 2013). Another possibility is that STAG2 stabilizes the positioning of cohesin rings on centromeric chromatin to create platforms for the appropriate phosphorylation of histone subunits and the recruitment of centromeric-binding proteins.…”

Section: Resultsmentioning

confidence: 99%

STAG2 promotes error correction in mitosis by regulating kinetochore-microtubule attachments

Kleyman

Kabeche

Compton

2014

Journal of Cell Science

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Mutations in the STAG2 gene are present in ,20% of tumors from different tissues of origin. STAG2 encodes a subunit of the cohesin complex, and tumors with loss-of-function mutations are usually aneuploid and display elevated frequencies of lagging chromosomes during anaphase. Lagging chromosomes are a hallmark of chromosomal instability (CIN) arising from persistent errors in kinetochore-microtubule (kMT) attachment. To determine whether the loss of STAG2 increases the rate of formation of kMT attachment errors or decreases the rate of their correction, we examined mitosis in STAG2-deficient cells. STAG2 depletion does not impair bipolar spindle formation or delay mitotic progression. Instead, loss of STAG2 permits excessive centromere stretch along with hyperstabilization of kMT attachments. STAG2-deficient cells display mislocalization of Bub1 kinase, Bub3 and the chromosome passenger complex. Importantly, strategically destabilizing kMT attachments in tumor cells harboring STAG2 mutations by overexpression of the microtubule-destabilizing enzymes MCAK (also known as KIF2C) and Kif2B decreased the rate of lagging chromosomes and reduced the rate of chromosome missegregation. These data demonstrate that STAG2 promotes the correction of kMT attachment errors to ensure faithful chromosome segregation during mitosis.

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Section: Resultsmentioning

confidence: 99%

STAG2 promotes error correction in mitosis by regulating kinetochore-microtubule attachments

Kleyman

Kabeche

Compton

2014

Journal of Cell Science

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“…Liu et al, 2015). However, it remains unclear whether the conserved centromere localization of the CPC is required for its early mitotic functions (Caldas et al, 2013; Campbell and Desai, 2013; F. Wang et al, 2010; Yue et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Distinct Roles of the Chromosomal Passenger Complex in the Detection of and Response to Errors in Kinetochore-Microtubule Attachment

et al. 2017

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Summary The Chromosomal Passenger Complex (CPC) localizes to centromeres in early mitosis to activate its subunit Aurora B kinase. However, it is unclear if centromeric CPC localization contributes to CPC functions beyond Aurora B activation. Here, we show that an activated CPC that cannot localize to centromeres supports functional assembly of the outer kinetochore, but is unable to correct errors in kinetochore-microtubule attachment in Xenopus egg extracts. We find that CPC has two distinct roles at centromeres: one to properly phosphorylate Ndc80 to regulate attachment, and a second, conserved kinase-independent role in the proper composition of inner kinetochore proteins. Although a fully assembled inner kinetochore is not required for outer kinetochore assembly, we find it is essential to recruit tension indicators, such as BubR1 and 3F3/2, to erroneous attachments. Thus, centromeric CPC is necessary for tension-dependent removal of erroneous attachments, and for the kinetochore composition required to detect tension loss.

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“…Both BubR1 and BuGZ function within complex regulatory pathways to affect kinetochore phosphoregulation, and targeting other mitotic proteins in these pathways may yield GBM specific cell death. These include kinase activities of Mps1 (55-57), Bub1 (13-15), PKM2 (58) and Plk1 (11). As discussed previously, Bub1 activation of ABK activity requires BuGZ through an unknown mechanism.…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

“…BubR1 recruits the phosphatase PP2A to kinetochores to dephosphorylate ABK substrates and promote KT-MT attachment stability (Figure 1) (10-12). In addition, Bub1 has been implicated in regulating KT-MT attachments both through the recruitment of ABK to centromeres via phosphorylation of histone H2A and through promotion of ABK activity at kinetochores independently of its centromere accumulation (Figure 1) (13-15). While SAC activity and SAC protein levels have been commonly characterized in cancers, their secondary role in regulating KT-MT attachments has only recently been evaluated.…”

Section: Introductionmentioning

confidence: 99%

“…Inhibition of BuGZ results in loss of both Bub3 and another Bub3 binding partner, Bub1, from kinetochores, but does not result in loss of BubR1 from kinetochores (39). Localized Bub1 kinase activity helps mediate proper KT-MT attachments through recruitment and activation of ABK to centromeres and kinetochores (13-15). Consistent with BuGZ affecting Bub1 kinetochore localization in GBM isolates, we observe chromosome alignment defects in transformed cells with BuGZ-knockdown, but not in untransformed cells.…”

Section: Introductionmentioning

confidence: 99%

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Molecular Pathways: Regulation and Targeting of Kinetochore–Microtubule Attachment in Cancer

Herman

Toledo

Olson

et al. 2015

Clinical Cancer Research

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Kinetochores are large protein structures assembled on centromeric DNA during mitosis that bind to microtubules of the mitotic spindle to orchestrate and power chromosome movements. Deregulation of kinetochore-microtubule (KT-MT) attachments has been implicated in driving chromosome instability and cancer evolution; however, the nature and source of KT-MT attachment defects in cancer cells remain largely unknown. Here we highlight recent findings suggesting that oncogene-driven changes in kinetochore regulation occur in Glioblastoma multiforme (GBM) and possibly other cancers exhibiting chromosome instability, giving rise to novel therapeutic opportunities. In particular, we consider the GLE2p-binding sequence (GLEBS) domains of BubR1 and the newly discovered BuGZ, two kinetochore associated proteins, as candidate therapeutic targets for GBM.

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KNL1 facilitates phosphorylation of outer kinetochore proteins by promoting Aurora B kinase activity

Abstract: KNL1 is essential for efficient kinetochore–microtubule attachment dynamics during mitosis, in part through promotion of Bub1-mediated targeting of Aurora B to the kinetochore.

Cited by 70 publications

References 46 publications

STAG2 promotes error correction in mitosis by regulating kinetochore-microtubule attachments

STAG2 promotes error correction in mitosis by regulating kinetochore-microtubule attachments

Distinct Roles of the Chromosomal Passenger Complex in the Detection of and Response to Errors in Kinetochore-Microtubule Attachment

Molecular Pathways: Regulation and Targeting of Kinetochore–Microtubule Attachment in Cancer

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