The Role of Hklp2 in the Stabilization and Maintenance of Spindle Bipolarity

Abstract

Spindle bipolarity relies on a fine balance of forces exerted by various molecular motors [1-4]. In most animal cells, spindle bipolarity requires sustained outward forces to push the spindle poles apart, an activity that is provided by Eg5, a conserved homotetrameric plus-end-directed kinesin that crosslinks and slides antiparallel microtubules apart [5]. These pushing forces are balanced by inward minus-end-directed forces. Impairing both Eg5 and dynein restores the formation of functional bipolar spindles [4], although the mechanism at play is far from clear. The current model also fails to explain why in some systems Eg5 inhibition does not promote bipolar spindle collapse [6, 7] or why increasing Eg5 levels does not interfere with bipolar spindle assembly [8]. Moreover, the C. elegans Eg5 ortholog is not required for bipolar spindle formation [9]. We show here that the kinesin Hklp2 participates in the assembly and stabilization of the bipolar spindle. Hklp2 localizes to the mitotic microtubules in a TPX2-dependent manner and to the chromosomes through Ki67. Our data indicate that its mechanism of action is clearly distinct from and complementary to that of Eg5, providing an additional understanding of the mechanism driving the formation and maintenance of the bipolar spindle.

Kinesin-12 motors cooperate to suppress microtubule catastrophes and drive the formation of parallel microtubule bundles

“…We therefore propose that the main task of hKif15 motors in vivo is to actively reorganize microtubules into parallel bundles. This would be consistent with the reported enrichment of hKif15 motors to kinetochore fibers (9)(10)(11). Furthermore, depletion of hKif15 reduces k-fiber length in vivo (11).…”

“…As in centrosome separation, Eg5 generates an outward pushing force by sliding apart antiparallel overlapping nonkinetochore microtubules. However, Eg5 is not essential for spindle maintenance because a second motor, Kinesin-12 Kif15, can compensate for loss of Eg5 activity (9,10). Kif15 is not required for centrosome separation in prophase, although overexpression of the motor can also drive spindle formation during prometaphase-even in the absence of Eg5 activity (9,11).…”

Resistance is not futile: Surviving Eg5 inhibition

“…1), and can be conferred by simple Kif15 overexpression. 3,4 These findings are consistent with the idea that Kif15 can compensate for a loss of Eg5 activity, and may indicate that Eg5 monotherapies will inevitably fail due to the existence of an auxiliary Kif15-dependent spindle assembly pathway. A corollary of this idea is that a combination therapy involving both K5Is and Kif15 inhibitors would be essential to prevent K5I resistance and increase the therapeutic efficacy of anti-mitotics that target spindle assembly.…”

Prime movers: the mechanochemistry of mitotic kinesins

“…In fact, it is has been proposed that they may counteract this force by suppressing spindle microtubule dynamics 112 . KIF15 has also been considered a chromokinesin as it is targeted to chromosome arms by binding Ki-67 81 . Loss of this chromosome-bound pool of KIF15 is associated with some congression problems 81 .…”

“…KIF15 has also been considered a chromokinesin as it is targeted to chromosome arms by binding Ki-67 81 . Loss of this chromosome-bound pool of KIF15 is associated with some congression problems 81 .…”