Hsp72 is targeted to the mitotic spindle by Nek6 to promote K-fiber assembly and mitotic progression |
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| Authors: | Laura O’Regan Josephina Sampson Mark W Richards Axel Knebel Daniel Roth Fiona E Hood Anne Straube Stephen J Royle Richard Bayliss Andrew M Fry |
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| Institution: | 1Department of Biochemistry, University of Leicester, Leicester LE1 9HN, England, UK;2Kinasource Ltd, The Sir James Black Center, Dundee DD1 5EH, Scotland, UK;3Centre for Mechanochemical Cell Biology, Warwick Medical School, Coventry CV4 7AL, England, UK;4Department of Cellular and Molecular Physiology, University of Liverpool, Liverpool L69 3BX, England, UK |
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| Abstract: | Hsp70 proteins represent a family of chaperones that regulate cellular homeostasis and are required for cancer cell survival. However, their function and regulation in mitosis remain unknown. In this paper, we show that the major inducible cytoplasmic Hsp70 isoform, Hsp72, is required for assembly of a robust bipolar spindle capable of efficient chromosome congression. Mechanistically, Hsp72 associates with the K-fiber–stabilizing proteins, ch-TOG and TACC3, and promotes their interaction with each other and recruitment to spindle microtubules (MTs). Targeting of Hsp72 to the mitotic spindle is dependent on phosphorylation at Thr-66 within its nucleotide-binding domain by the Nek6 kinase. Phosphorylated Hsp72 concentrates on spindle poles and sites of MT–kinetochore attachment. A phosphomimetic Hsp72 mutant rescued defects in K-fiber assembly, ch-TOG/TACC3 recruitment and mitotic progression that also resulted from Nek6 depletion. We therefore propose that Nek6 facilitates association of Hsp72 with the mitotic spindle, where it promotes stable K-fiber assembly through recruitment of the ch-TOG–TACC3 complex. |
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