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

Aaron C. Groen, Daniel Needleman, Clifford Brangwynne, Christian Gradinau, Brandon Fowler, Ralph Mazitschek, Timothy J. Mitchison

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

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 γ-tubulin became redistributed to the spindle equator, suggesting that proper kinesin-5 function is required for pole assembly.

Original languageEnglish (US)
Pages (from-to)2293-2300
Number of pages8
JournalJournal of cell science
Volume121
Issue number14
DOIs
StatePublished - Jul 15 2008
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Cell Biology

Keywords

  • Kinesin-5
  • Mitosis
  • Small-molecule inhibitor
  • Xenopus-extract spindles

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    Groen, A. C., Needleman, D., Brangwynne, C., Gradinau, C., Fowler, B., Mazitschek, R., & Mitchison, T. J. (2008). A novel small-molecule inhibitor reveals a possible role of kinesin-5 in anastral spindle-pole assembly. Journal of cell science, 121(14), 2293-2300. https://doi.org/10.1242/jcs.024018