KIF15 nanomechanics and kinesin inhibitors, with implications for cancer chemotherapeutics

Milic, Bojan; Chakraborty, Anirban; Han, Ke; Bassik, Michael C.; Block, Steven M.

doi:10.1073/pnas.1801242115

Cited by 46 publications

(29 citation statements)

References 76 publications

(168 reference statements)

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“…For these experiments, we used two Kif15 inhibitors that act by different mechanisms. Kif15-IN-1 arrests the motor in a microtubule-bound state, and thus blocks motility without disrupting its ability to crosslink microtubules (Milic et al , 2018) . By contrast, GW108X prevents the motor domain of Kif15 from binding the microtubule track, thus preventing the formation of microtubule crosslinks .…”

Section: Kif15 Binds and Crosslinks K-fiber Microtubules To Promote Kmentioning

confidence: 99%

“…Through this mechanism, Kif15 can antagonize inward forces generated by minus-end-directed motors, thereby enforcing spindle bipolarity, and separating centrosomes in cells adapted to grow in the presence of Eg5 inhibitors (Raaijmakers et al , 2012;Sturgill and Ohi, 2013) . This redundancy between Kif15 and Eg5 is of interest as a potential factor in the disappointing ineffectiveness thus far of Eg5 inhibitors as cancer therapeutics (Tanenbaum et al , 2009;Rath and Kozielski, 2012;Milic et al , 2018;Dumas et al , 2019) . It is particularly notable since Kif15 overexpression results in lagging chromosomes (Malaby et al , 2019) , and is upregulated in a number of cancers (Ma et al , 2014;Wang et al , 2017;Qiao et al , 2018;Yu et al , 2019;Zhao et al , 2019;Sun et al , 2020;Terribas et al , 2020) .…”

Section: Introductionmentioning

confidence: 99%

“…Through this mechanism, Kif15 can antagonize inward forces generated by minus-end-directed motors, thereby enforcing spindle bipolarity, and separating centrosomes in cells adapted to grow in the presence of Eg5 inhibitors (Sturgill and Ohi 2013;Raaijmakers et al 2012) . This redundancy between Kif15 and Eg5 is of particular interest as a potential factor in the disappointing ineffectiveness thus far of Eg5 inhibitors as cancer therapeutics (Tanenbaum et al 2009;Milic et al 2018;Dumas et al 2019;Rath and Kozielski 2012) . Furthermore, Kif15 upregulation is found in a number of cancer types and can result in rapid cancer cell proliferation (Wang et al 2017;Zhao et al 2019;Yu et al 2019;Qiao et al 2018;Sun et al 2020;Terribas et al 2020;Ma et al 2014) .…”

Section: Introductionmentioning

confidence: 99%

“…To probe the role of Kif15 in k-fiber integrity, we test the effect of two Kif15 inhibitors (Kif15-IN-1 and GW108X) on k-fiber splaying. Kif15-IN-1 has been suggested to stabilize a microtubule-bound rigor state (Milic et al 2018) , whereas GW108X blocks the attachment of Kif15's motor head to microtubules (Dumas et al 2019) . Ablation experiments in cells treated with GW108X reveal a heightened sensitivity to these minus-end-directed forces.…”

Section: Introductionmentioning

confidence: 99%

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K-fiber bundles in the mitotic spindle are mechanically reinforced by Kif15

Begley

Solon

Davis

et al. 2020

Preprint

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AbstractThe mitotic spindle, a self-constructed microtubule-based machine, segregates chromosomes into two eventual daughter nuclei. In mammalian cells, microtubule bundles called kinetochore-fibers (k-fibers) anchor chromosomes within the spindle. Chromosome segregation thus depends on the mechanical integrity of k-fibers. Here, we investigate the physical and molecular basis of k-fiber bundle cohesion. We sever k-fibers using laser ablation, thereby detaching them from poles and testing the contribution of pole-localized force generation to k-fiber cohesion. We then measure the physical response of the remaining kinetochore-bound segments of the k-fibers. We observe that microtubules within ablated k-fibers often, but not always, splay apart from their minus-ends. Furthermore, we find that minus-end clustering forces induced in response to ablation seem at least partially responsible for k-fiber splaying. We also investigate the role of the putative k-fiber-binding kinesin-12 Kif15. We find that pharmacological inhibition of Kif15 microtubule binding reduces k-fiber mechanical integrity. In contrast, inhibition of its motor activity but not its microtubule binding does not greatly affect splaying. Altogether, the data suggest that forces holding k-fibers together are of similar magnitude to other spindle forces, and that Kif15, acting as a microtubule crosslinker, helps fortify and repair k-fibers. This feature of Kif15 may help support robust k-fiber function and prevent chromosome segregation errors.

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Section: Kif15 Binds and Crosslinks K-fiber Microtubules To Promote Kmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Through this mechanism, Kif15 can antagonize inward forces generated by minus-end-directed motors, thereby enforcing spindle bipolarity, and separating centrosomes in cells adapted to grow in the presence of Eg5 inhibitors (Sturgill and Ohi 2013;Raaijmakers et al 2012) . This redundancy between Kif15 and Eg5 is of particular interest as a potential factor in the disappointing ineffectiveness thus far of Eg5 inhibitors as cancer therapeutics (Tanenbaum et al 2009;Milic et al 2018;Dumas et al 2019;Rath and Kozielski 2012) . Furthermore, Kif15 upregulation is found in a number of cancer types and can result in rapid cancer cell proliferation (Wang et al 2017;Zhao et al 2019;Yu et al 2019;Qiao et al 2018;Sun et al 2020;Terribas et al 2020;Ma et al 2014) .…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

K-fiber bundles in the mitotic spindle are mechanically reinforced by Kif15

Begley

Solon

Davis

et al. 2020

Preprint

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“…Unlike Eg5, there are not many inhibitors for Kif15. One of the inhibitor identified as Kif15‐IN‐1 is reported to induce significant cell death in cancer cells when combined with the Eg5 inhibitor ispinesib …”

Section: Introductionmentioning

confidence: 99%

Benserazide Perturbs Kif15‐kinesin Binding Protein Interaction with Prolonged Metaphase and Defects in Chromosomal Congression: A Study Based on in silico Modeling and Cell Culture

Sebastian

Rathinasamy

2019

Molecular Informatics

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The interaction of Kif15 with kinesin binding protein (KBP) is critical for its microtubule localization, bundling of kinetochore microtubules and proper alignment of chromosomes at the metaphase plate. The Kif15‐KBP structure was prepared from the crystal structure of Kif15 and nonhomologous model of KBP through docking. Benserazide was retrieved when we did a screening of the ZINC Drug Database using the pharmacophore model generated from the potential binding site on Kif15 in an effort to identify molecules for repurposing as Kif15 inhibitors. Live cell imaging of HeLa cells revealed that benserazide delayed metaphase to anaphase‐onset by 47±10 min compared to control cells. Benserazide treatment perturbed the kinetochore and microtubule interaction and inhibited the proliferation of HeLa cells with an IC50 of 101 μM with a mitotic block of 12 %. It did not bind to tubulin in the in vitro assays suggesting that the observed effects could be due to its perturbation of Kif15‐KBP interaction.

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