A mitotic SKAP isoform regulates spindle positioning at astral microtubule plus ends

Kern, David; Nicholls, Peter K.; Page, David C.; Cheeseman, Iain M.

doi:10.1083/jcb.201510117

Cited by 38 publications

(78 citation statements)

References 52 publications

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“…This effect is not caused by astral microtubule shortening; unlike disruption of EB-1 itself, deletion of the SKAP EB-1 motif does not affect astral microtubule length (Kern et al, 2016;Toyoshima and Nishida, 2007). Another potential explanation for mispositioning, namely that plus tips carry spindle-orienting factors to the cortex, is ruled out by the observation that cortical dynein is still observed in SKAPΔEB-1 cells (Kern et al, 2016). However, an additional possibility to consider is that the Astrin/SKAP complex mediates the interaction between astral microtubules and the cortical machinery, analogous to the role played by the complex at kinetochores.…”

Section: Introductionmentioning

confidence: 99%

“…SKAP and Astrin form a complex that is known to play a role at kinetochores, which mediate the attachment between spindle microtubules and chromosomes (Dunsch et al, 2011;Schmidt et al, 2010). Their astral microtubule localization is probably determined directly by SKAP, which has an end-binding protein 1 (EB-1) motif that is required for plus-end localization (Kern et al, 2016). Intriguingly, in single HeLa cells, mutation of the EB-1-binding motif (yielding SKAPΔEB-1) causes spindle mispositioning (Kern et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

“…Astral microtubule plus tips: a consideration for spindle orientation A recent study identified two proteins -small kinetochore associated protein (SKAP) and Astrin -at astral microtubule plus ends, and implicated these proteins in spindle orientation (Kern et al, 2016). SKAP and Astrin form a complex that is known to play a role at kinetochores, which mediate the attachment between spindle microtubules and chromosomes (Dunsch et al, 2011;Schmidt et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…Intriguingly, in single HeLa cells, mutation of the EB-1-binding motif (yielding SKAPΔEB-1) causes spindle mispositioning (Kern et al, 2016). This effect is not caused by astral microtubule shortening; unlike disruption of EB-1 itself, deletion of the SKAP EB-1 motif does not affect astral microtubule length (Kern et al, 2016;Toyoshima and Nishida, 2007). Another potential explanation for mispositioning, namely that plus tips carry spindle-orienting factors to the cortex, is ruled out by the observation that cortical dynein is still observed in SKAPΔEB-1 cells (Kern et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

“…Their astral microtubule localization is probably determined directly by SKAP, which has an end-binding protein 1 (EB-1) motif that is required for plus-end localization (Kern et al, 2016). Intriguingly, in single HeLa cells, mutation of the EB-1-binding motif (yielding SKAPΔEB-1) causes spindle mispositioning (Kern et al, 2016). This effect is not caused by astral microtubule shortening; unlike disruption of EB-1 itself, deletion of the SKAP EB-1 motif does not affect astral microtubule length (Kern et al, 2016;Toyoshima and Nishida, 2007).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Spindle orientation: a question of complex positioning

2017

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The direction in which a cell divides is determined by the orientation of its mitotic spindle at metaphase. Spindle orientation is therefore important for a wide range of developmental processes, ranging from germline stem cell division to epithelial tissue homeostasis and regeneration. In multiple cell types in multiple animals, spindle orientation is controlled by a conserved biological machine that mediates a pulling force on astral microtubules. Restricting the localization of this machine to only specific regions of the cortex can thus determine how the mitotic spindle is oriented. As we review here, recent findings based on studies in tunicate, worm, fly and vertebrate cells have revealed that the mechanisms for mediating this restriction are surprisingly diverse.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Spindle orientation: a question of complex positioning

2017

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Creation and testing of a new, local microtubule‐disruption tool based on the microtubule‐severing enzyme, katanin p60

2018

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Current methods to disrupt the microtubule cytoskeleton do not easily provide rapid, local control with standard cell manipulation reagents. Here, we develop a new microtubule-disruption tool based on katanin p60 severing activity and demonstrate proof-of-principle by targeting it to kinetochores in Drosophila melanogaster S2 cells. Specifically, we show that human katanin p60 can remove microtubule polymer mass in S2 cells and an increase in misaligned chromosomes when globally overexpressed. When katanin p60 was targeted to the kinetochores via Mis12, we were able to recapitulate the misalignment only when using a phosphorylation-resistant mutant katanin p60. Our results demonstrate that targeting an active version of katanin p60 to the kinetochore can reduce the fidelity of achieving full chromosome alignment in metaphase and could serve as a microtubule disruption tool for the future.

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KNSTRN Is a Prognostic Biomarker That Is Correlated with Immune Infiltration in Breast Cancer and Promotes Cell Cycle and Proliferation

Zhang,

Xiao,

Zhou

et al. 2024

Biochem Genet

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Kinetochore-localized astrin/SPAG5-binding protein (KNSTRN) promotes the progression of bladder cancer and lung adenocarcinoma. However, its expression and biological function in breast cancer remain largely unknown. Therefore, this study aimed to analyze KNSTRN expression, prognoses, correlation with immune infiltration, expression-associated genes, and regulated signaling pathways to characterize its role in regulating the cell cycle using both bioinformatics and in vitro functional experiments. Analyses of The Cancer Genome Atlas, Gene Expression Omnibus, TIMER, and The Human Protein Atlas databases revealed a significant upregulation of KNSTRN transcript and protein levels in breast cancer. Kaplan–Meier survival analyses demonstrated a significant association between high expression of KNSTRN and poor overall survival, relapse-free survival, post-progression survival, and distant metastases-free survival in patients with breast cancer. Furthermore, multivariate Cox regression analyses confirmed that KNSTRN is an independent prognostic factor for breast cancer. Immune infiltration analysis indicated a positive correlation between KNSTRN expression and T regulatory cell infiltration while showing a negative correlation with Tgd and natural killer cell infiltration. Gene set enrichment analysis along with single-cell transcriptome data analysis suggested that KNSTRN promoted cell cycle progression by regulating the expression of key cell cycle proteins. The overexpression and silencing of KNSTRN in vitro, respectively, promoted and inhibited the proliferation of breast cancer cells. The overexpression of KNSTRN enhanced the expression of key cell cycle regulators, including CDK4, CDK6, and cyclin D3, thereby accelerating the G1/S phase transition and leading to aberrant proliferation of breast cancer cells. In conclusion, our study demonstrates that KNSTRN functions as an oncogene in breast cancer by regulating immune response, promoting G1/S transition, and facilitating breast cancer cell proliferation. Moreover, KNSTRN has potential as a molecular biomarker for diagnostic and prognostic prediction in breast cancer.

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A mitotic SKAP isoform regulates spindle positioning at astral microtubule plus ends

Cited by 38 publications

References 52 publications

Spindle orientation: a question of complex positioning

Spindle orientation: a question of complex positioning

Creation and testing of a new, local microtubule‐disruption tool based on the microtubule‐severing enzyme, katanin p60

KNSTRN Is a Prognostic Biomarker That Is Correlated with Immune Infiltration in Breast Cancer and Promotes Cell Cycle and Proliferation

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