Kif15 functions as an active mechanical ratchet

McHugh, Toni; Drechsler, Hauke; McAinsh, Andrew D.; Carter, Nicolas J; Cross, Robert A.

doi:10.1091/mbc.e18-03-0151

Cited by 16 publications

(16 citation statements)

References 21 publications

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“…The effect is maintained if capturing of the vesicles by the tether is impaired – we suggest that could be an explanation of a suppression phenotype. The picture is different when Kifs having lower velocity (100 nm/sec) are depleted, such as Kif11 (Guo et al, 2018, 2019) or loaded Kif15 that readily detaches from MTs under these conditions (McHugh et al, 2018). Then, the balance is shifted toward the distribution of vesicles away from the Golgi complex, likely, along the tracts of microtubules, followed by Golgi reassembly at distant sites (“fragmentation phenotype”).…”

Section: Resultsmentioning

confidence: 99%

Epistatic Analysis of the Contribution of Rabs and Kifs to CATCHR Family Dependent Golgi Organization

Liu

Majeed

Grigaitis

et al. 2019

Front. Cell Dev. Biol.

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Multisubunit members of the CATCHR family: COG and NRZ complexes, mediate intra-Golgi and Golgi to ER vesicle tethering, respectively. We systematically addressed the genetic and functional interrelationships between Rabs, Kifs, and the retrograde CATCHR family proteins: COG3 and ZW10, which are necessary to maintain the organization of the Golgi complex. We scored the ability of siRNAs targeting 19 Golgi-associated Rab proteins and all 44 human Kifs, microtubule-dependent motor proteins, to suppress CATCHR-dependent Golgi fragmentation in an epistatic fluorescent microscopy-based assay. We found that co-depletion of Rab6A, Rab6A’, Rab27A, Rab39A and two minus-end Kifs, namely KIFC3 and KIF25, suppressed both COG3- and ZW10-depletion-induced Golgi fragmentation. ZW10-dependent Golgi fragmentation was suppressed selectively by a separate set of Rabs: Rab11A, Rab33B and the little characterized Rab29. 10 Kifs were identified as hits in ZW10-depletion-induced Golgi fragmentation, and, in contrast to the double suppressive Kifs, these were predominantly plus-end motors. No Rabs or Kifs selectively suppressed COG3-depletion-induced Golgi fragmentation. Protein-protein interaction network analysis indicated putative direct and indirect links between suppressive Rabs and tether function. Validation of the suppressive hits by EM confirmed a restored organization of the Golgi cisternal stack. Based on these outcomes, we propose a three-way competitive model of Golgi organization in which Rabs, Kifs and tethers modulate sequentially the balance between Golgi-derived vesicle formation, consumption, and off-Golgi transport.

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Section: Resultsmentioning

confidence: 99%

Epistatic Analysis of the Contribution of Rabs and Kifs to CATCHR Family Dependent Golgi Organization

Liu

Majeed

Grigaitis

et al. 2019

Front. Cell Dev. Biol.

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“…Mice weight and tumor length and width were recorded every 4 days for 6 weeks. The volume of tumors was estimated based on the measurement of length and width at 19,22,26,30,34 and 38 days post injection. Then all mice were anaesthetized by intraperitoneal injection of 0.7% sodium pentobarbital (10 μL/g) and the anaesthetized mice were placed under a Perkin Elmer IVIS Spectrum (Waltham, MA, USA) for in vivo bioluminescence imagine.…”

Section: Agingmentioning

confidence: 99%

GSG2 (Haspin) promotes development and progression of bladder cancer through targeting KIF15 (Kinase-12)

Chen

Zhao

et al. 2020

Aging

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Bladder cancer is the most commonly diagnosed malignant tumor in urological system worldwide. The relationship between GSG2 and bladder cancer has not been demonstrated and remains unclear. In this study, it was demonstrated that GSG2 was up-regulated in bladder cancer tissues compared with the normal tissues and its high expression was correlated with more advanced malignant grade and lower survival rate. Further investigations indicated that the overexpression/knockdown of GSG2 could promote/inhibit proliferation, colony formation and migration of bladder cancer cells, while inhibiting/promoting cell apoptosis. Moreover, knockdown of GSG2 could also suppress tumorigenicity of bladder cancer cells in vivo. RNA-sequencing followed by Ingenuity pathway analysis (IPA) was performed for exploring downstream of GSG2 and identified KIF15 as the potential target. Furthermore, our study revealed that knockdown of KIF15 could inhibit development of bladder cancer in vitro, and alleviate the GSG2 overexpression induced promotion of bladder cancer. In conclusion, our study showed, as the first time, GSG2 as a prognostic indicator and tumor promotor for bladder cancer, whose function was carried out probably through the regulation of KIF15.

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“…Yet, despite this inherent microtubule-binding activity, Kif15 requires its binding partner, Txp2, for recruitment to the spindle (Tanenbaum et al 2009) . Furthermore, in vitro data indicate that Tpx2 increases Kif15 microtubule binding while decreasing motor activity (McHugh et al 2018;Mann, Balchand, and Wadsworth 2017;Drechsler et al 2014) , emphasizing the importance of this interaction for Kif15 k-fiber bundling, and raising the question of how important motor activity is for this function.…”

Section: Introductionmentioning

confidence: 99%

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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Kif15 functions as an active mechanical ratchet

Cited by 16 publications

References 21 publications

Epistatic Analysis of the Contribution of Rabs and Kifs to CATCHR Family Dependent Golgi Organization

Epistatic Analysis of the Contribution of Rabs and Kifs to CATCHR Family Dependent Golgi Organization

GSG2 (Haspin) promotes development and progression of bladder cancer through targeting KIF15 (Kinase-12)

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

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