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First published online 17 June 2008
doi: 10.1242/jcs.024018

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A novel small-molecule inhibitor reveals a possible role of kinesin-5 in anastral spindle-pole assembly

¹ Harvard Medical School, Department of Systems Biology, 200 Longwood Avenue, WAB536, Boston, MA 02115, USA
² Marine Biological Laboratory, 7 MBL Street, Woods Hole, MA 02543, USA
³ Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA 02142, USA

^* Author for correspondence (e-mail: aaron_groen{at}student.hms.harvard.edu)

Accepted 22 April 2008

The tetrameric plus-end-directed motor, kinesin-5, is essential for bipolar spindle assembly. Small-molecule inhibitors of kinesin-5 have been important tools for investigating its function, and some are currently under evaluation as anti-cancer drugs. Most inhibitors reported to date are `non-competitive' and bind to a specific site on the motor head, trapping the motor in an ADP-bound state in which it has a weak but non-zero affinity for microtubules. Here, we used a novel ATP-competitive inhibitor, FCPT, developed at Merck (USA). We found that it induced tight binding of kinesin-5 onto microtubules in vitro. Using Xenopus egg-extract spindles, we found that FCPT not only blocked poleward microtubule sliding but also selectively induced loss of microtubules at the poles of bipolar spindles (and not asters or monoasters). We also found that the spindle-pole proteins TPX2 and -tubulin became redistributed to the spindle equator, suggesting that proper kinesin-5 function is required for pole assembly.

Key words: Kinesin-5, Mitosis, Small-molecule inhibitor, Xenopus-extract spindles