Molecular mechanisms of kinesin-14 motors in spindle assembly and chromosome segregation

She, Zhen‐Yu; Yang, Wan-Xi

doi:10.1242/jcs.200261

Cited by 103 publications

(79 citation statements)

References 190 publications

(255 reference statements)

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“…Kinesin-14 proteins play critical roles in spindle pole formation in multiple organisms (Fink et al, 2009; Goshima et al, 2005a,b; Hatsumi and Endow, 1992b; Matuliene et al, 1999; Mountain et al, 1999; Sharp et al, 1999; She and Yang, 2017) and may be especially important in cells with centrosome amplification (Kwon et al, 2008), where they use their minus end–directed motor activity to help cluster those centrosomes into a bipolar spindle. Indeed, small-molecule inhibitors that target the human Kinesin-14, HSET, may be useful as targeted therapeutics in cancers with centrosome amplification (Watts et al, 2013); therefore, understanding Kinesin-14 function in the spindle is an important avenue of pursuit.…”

Section: Introductionmentioning

confidence: 99%

RanGTP induces an effector gradient of XCTK2 and importin α/β for spindle microtubule cross-linking

Ems-McClung

Emch

Zhang

et al. 2020

Journal of Cell Biology

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High RanGTP around chromatin is important for governing spindle assembly during meiosis and mitosis by releasing the inhibitory effects of importin α/β. Here we examine how the Ran gradient regulates Kinesin-14 function to control spindle organization. We show that Xenopus Kinesin-14, XCTK2, and importin α/β form an effector gradient that is highest at the poles and diminishes toward the chromatin, which is opposite the RanGTP gradient. Importin α and β preferentially inhibit XCTK2 antiparallel microtubule cross-linking and sliding by decreasing the microtubule affinity of the XCTK2 tail domain. This change in microtubule affinity enables RanGTP to target endogenous XCTK2 to the spindle. We propose that these combined actions of the Ran pathway are critical to promote Kinesin-14 parallel microtubule cross-linking to help focus spindle poles for efficient bipolar spindle assembly. Furthermore, our work illustrates that RanGTP regulation in the spindle is not simply a switch, but rather generates effector gradients where importins α and β gradually tune the activities of spindle assembly factors.

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Section: Introductionmentioning

confidence: 99%

RanGTP induces an effector gradient of XCTK2 and importin α/β for spindle microtubule cross-linking

Ems-McClung

Emch

Zhang

et al. 2020

Journal of Cell Biology

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“…Bipolar spindle assembly requires proper force-balance generated by kinesin-5 and kinesin-14 (Sharp et al, 2000;She and Yang, 2017;Tanenbaum and Medema, 2010). In fission yeast, ectopic overproduction of kinesin-14 Pkl1 or inactivation of kinesin-5…”

Section: The Lethality Of Fission Yeast Cells Overproducing Hset/kinementioning

confidence: 99%

Fission yeast cells overproducing HSET/KIFC1 provides a useful tool for identification and evaluation of human kinesin-14 inhibitors

Yukawa

Yamauchi

Kimura

et al. 2018

Preprint

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Many cancer cells contain more than two centrosomes, yet these cancer cells can form bipolar spindles and appear to proliferate normally, instead of committing lethal mitoses with multipolar spindles. It is shown that extra centrosomes are clustered into two pseudo-bipolar spindle poles, thereby escaping from multipolarity. Human kinesin-14 (HSET or KIFC1), a minus end-directed motor, plays a crucial role in centrosome clustering and as such, HSET is essential for cell viability only in cancer cells with supernumerary centrosomes, but not in non-transformed cells. Accordingly, HSET is deemed to be an efficient chemotherapeutic target to selectively kill cancer cells. Recently, three HSET inhibitors (AZ82, CW069 and SR31527) have been reported, but their specificity, efficacy and off-target cytotoxicity have not been evaluated rigorously. Here we show that these inhibitors on their own are cytotoxic to fission yeast, suggesting that they have other targets in vivo except for kinesin-14. Nonetheless, intriguingly, AZ82 can neutralize overproduced HSET and partially rescue its lethality. This methodology of protein overproduction in fission yeast provides a convenient, functional assay system by which to screen for not only selective human kinesin-14 inhibitors but also those against other molecules of interest.

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“…The other reason is more active; in the absence of Kinesin-5, opposing motors such as Kinesin-14 or Dynein predominantly prevent centrosome/SPB separation by generating excessive inward force. As such, in many of the systems examined, inactivation of Kinesin-14 or Dynein rescues otherwise lethal Kinesin-5 inhibition (Bieling et al, 2010; Civelekoglu-Scholey et al, 2010; Ferenz et al, 2009; Gaglio et al, 1996; Gatlin et al, 2009; Mitchison et al, 2005; Mountain et al, 1999; O'Connell et al, 1993; Pidoux et al, 1996; Salemi et al, 2013; Saunders et al, 1997; Sharp et al, 2000a; Sharp et al, 1999; She and Yang, 2017; Tanenbaum et al, 2008; Tao et al, 2006; Walczak et al, 1998; Wang et al, 2015).…”

Section: Introductionmentioning

confidence: 98%

“…In many organisms, including fission yeast, human beings and plants, multiple Kinesin-14 proteins are encoded in the genome (fission yeast Pkl1 and Klp2, human HSET/KifC1, KifC2, KifC3 and Kif25 and Arabidopsis AKT and KCBP) (Decarreau et al, 2017; Noda et al, 2001; Pidoux et al, 1996; She and Yang, 2017; Troxell et al, 2001; Yamada et al, 2017). Even in budding yeast that contains the single Kinesin-14 Kar3, it forms two different complexes in a cell by interacting with distinct partners, Cik1 and Vik1 (Manning et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

Two spatially distinct Kinesin-14 Pkl1 and Klp2 generate collaborative inward forces against Kinesin-5 Cut7 inS. pombe

Yukawa

Yamada

Yamauchi

et al. 2017

Preprint

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Keywords: fission yeast/force generation/kinesin/mitotic bipolar spindle/spindle pole body Abbreviations used: GFP-binding protein, GBP; Msd1-Wdr8-Pkl1 complex, MWP complex; spindle pole body, SPB; temperature sensitive, ts; the γ -tubulin complex, γ -TuC 2 SUMMARY STATEMENT Proper force-balance generated by Kinesin-5 and Kinesin-14 is crucial for spindle bipolarity. Two fission yeast Kinesin-14s localize to different structures, thereby collaboratively producing inward forces against Kinesin-5-mediated outward force. ABSTRACT Kinesin motors play central roles in bipolar spindle assembly. In many eukaryotes, spindle pole separation is driven by Kinesin-5 that generates outward force. This outward force is balanced by antagonistic inward force elicited by Kinesin-14 and/or Dynein. In fission yeast, two Kinesin-14s, Pkl1 and Klp2, play an opposing role against Kinesin-5/Cut7. However, how these two Kinesin-14s coordinate individual activities remains elusive. Here we show that while deletion of either pkl1 or klp2 rescues temperature sensitive cut7 mutants, only pkl1 deletion can bypass the lethality caused by cut7 deletion. Pkl1 is tethered to the spindle pole body, while Klp2 is localized along the spindle microtubule. Forced targeting of Klp2 to the spindle pole body, however, compensates for Pkl1 functions, indicating that cellular localizations, rather than individual motor specificities, differentiate between the two Kinesin-14s. Interestingly, human Kinesin-14/HSET can replace either Pkl1 or Klp2. Moreover, overproducing HSET induces monopolar spindles, reminiscent of the phenotype of Cut7 inactivation.Taken together, this study has uncovered the biological mechanism of how two different Kinesin-14s exert their antagonistic roles against Kinesin-5 in a spatially distinct manner.3

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Molecular mechanisms of kinesin-14 motors in spindle assembly and chromosome segregation

Cited by 103 publications

References 190 publications

RanGTP induces an effector gradient of XCTK2 and importin α/β for spindle microtubule cross-linking

RanGTP induces an effector gradient of XCTK2 and importin α/β for spindle microtubule cross-linking

Fission yeast cells overproducing HSET/KIFC1 provides a useful tool for identification and evaluation of human kinesin-14 inhibitors

Two spatially distinct Kinesin-14 Pkl1 and Klp2 generate collaborative inward forces against Kinesin-5 Cut7 inS. pombe

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