The Human Kinesin Kif18A Is a Motile Microtubule Depolymerase Essential for Chromosome Congression

Abstract

These studies identify Kif18A as a dual-functional kinesin and a key component of chromosome congression in mammalian cells.

Prime movers: the mechanochemistry of mitotic kinesins

“…KIF18A operates at kinetochores 106 , whereas KIF18B is found on astralmicrotubules 107,108 . Some of the members of the kinesin-8 family are highly processive, and initial work on S. cerevisiae Kip3 indicated that it has depolymerase activity 49,109 .…”

“…KIF18A can also make tubulin rings 113 and has an extended loop-2 reminiscent of the kinesin-13 family (BOX 2), which supports the idea that it can bend tubulin to drive depolymerization. These effects on microtubule dynamics likely cause the reported changes in the speed and amplitude of kinetochore oscillations following depletion of KIF18A, and the resulting severe chromosome congression defect 106,114,115 . The first single molecule mechanics data for KIF18A were recently reported,…”

Role and regulation of kinesin-8 motors through the cell cycle

“…In human cells the expression of Kif18A and Kif18B mirrors that of Cyclin B1 being low or undetectable in G1 and high at G2/M phase (Mayr et al 2007;Lee et al 2010). Although it is not known how Kif18A levels are modulated, it is intriguing that Kif18A interacts with the anaphase promoting complex (APC/C) (Sedgwick et al 2013), the E3 ubiquitin ligase that is responsible for Cyclin B1 destruction.…”

“…During mitosis many, but not all, of these proteins localise to the plus end of kinetochore microtubules indicative of a conserved mitotic function. Suppressing the expression or deleting these motors leads an increase in mitotic spindle length, a failure of chromosomes to align on the metaphase plate and a protracted delay in the onset of anaphase, due to activation of the spindle assembly checkpoint (Straight et al 1998;Rischitor et al 2004;Goshima et al 2005;Mayr et al 2007;Stumpff et al 2008;Wargacki et al 2010;Jaqaman et al 2010). During early mitosis, sister kinetochore pairs undergo rapid and co-ordinated oscillations, alternating between moving towards and away from the spindle pole (Skibbens et al 1993;Rieder and Salmon 1994).…”

“…During interphase fission yeast microtubule bundles, which are nucleated from MTOCs (microtubule organising centres) surrounding a centrally located nucleus, grow towards both cell ends to deposit factors that are required for the maintenance of cell polarity and to maintain the nucleus in the centre of the cell (Martin 2009;Chang and Nurse 1996;Tran et al 2000Tran et al , 2001. In the absence of the Klp5 or Klp6 motors some interphase Savoian et al (2004) Spindle length Gandhi et al (2004); Savoian and Glover (2010) Mitochondrial distribution Gandhi et al (2004) Central spindle stability and formation Gatt et al (2005) Spindle elongation Wang et al (2010) Homo sapiens KIF18A Chromosome congression Mayr et al (2007) Chromosome oscillation Stumpff et al (2008) West et al (2001) microtubules fail to pause at the cell end and continue to grow, resulting in long microtubules that bend around the cell cortex. This results in a defect in cell polarity particularly in elongated cells (West et al 2001).…”