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Mitotic phosphorylation by NEK6 and NEK7 reduces the microtubule affinity of EML4 to promote chromosome congression

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Adib, Rozita, Montgomery, Jessica, Atherton, Joseph, O'Regan, Laura, Richards, Mark W., Straatman, Kees, Roth, Daniel, Straube, Anne, Bayliss, Richard, Moores, Carolyn and Fry, Andrew M. (2019) Mitotic phosphorylation by NEK6 and NEK7 reduces the microtubule affinity of EML4 to promote chromosome congression. Science Signalling, 12 (594). eaaw2939. doi:10.1126/scisignal.aaw2939 ISSN 1937-9145.

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Official URL: https://doi.org/10.1126/scisignal.aaw2939

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Abstract

EML4 is a microtubule-associated protein that promotes microtubule stability. We investigated its regulation across the cell cycle and found that EML4 was distributed as punctate foci along the microtubule lattice in interphase but exhibited reduced association with spindle microtubules in mitosis. Microtubule sedimentation and cryo–electron microscopy with 3D reconstruction revealed that the basic N-terminal domain of EML4 mediated its binding to the acidic C-terminal tails of α- and β-tubulin on the microtubule surface. The mitotic kinases NEK6 and NEK7 phosphorylated the EML4 N-terminal domain at Ser144 and Ser146 in vitro, and depletion of these kinases in cells led to increased EML4 binding to microtubules in mitosis. An S144A-S146A double mutant not only bound inappropriately to mitotic microtubules but also increased their stability and interfered with chromosome congression. In addition, constitutive activation of NEK6 or NEK7 reduced the association of EML4 with interphase microtubules. Together, these data support a model in which NEK6- and NEK7-dependent phosphorylation promotes the dissociation of EML4 from microtubules in mitosis in a manner that is required for efficient chromosome congression.

Item Type: Journal Article
Subjects: Q Science > QH Natural history
Q Science > QP Physiology
Divisions: Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Cell & Developmental Biology
Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH): Tubulins, Microtubules, Microtubules -- Stability, Chromosome inversions , Mitosis
Journal or Publication Title: Science Signalling
Publisher: American Association for the Advancement of Science
ISSN: 1937-9145
Official Date: 13 August 2019
Dates:
DateEvent
13 August 2019Published
17 July 2019Accepted
Volume: 12
Number: 594
Article Number: eaaw2939
DOI: 10.1126/scisignal.aaw2939
Status: Peer Reviewed
Publication Status: Published
Reuse Statement (publisher, data, author rights): “This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science Signalling on 12(594), eaaw2939. 13/08/2019. https://doi.org/10.1126/scisignal.aaw2939
Access rights to Published version: Restricted or Subscription Access
Copyright Holders: © 2019 The Authors
Date of first compliant deposit: 20 August 2019
Date of first compliant Open Access: 28 August 2019
RIOXX Funder/Project Grant:
Project/Grant IDRIOXX Funder NameFunder ID
16-0119Worldwide Cancer Researchhttp://dx.doi.org/10.13039/100011713
200870/Z/16/ZWellcome Trusthttp://dx.doi.org/10.13039/100010269
MR/R000352/1[MRC] Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
C24461/A2330Cancer Research UKhttp://dx.doi.org/10.13039/501100000289
UNSPECIFIEDLister Institute of Preventive Medicinehttp://dx.doi.org/10.13039/501100001255
UNSPECIFIED[BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268
UNSPECIFIEDUniversity Of Leedshttp://dx.doi.org/10.13039/501100000777
108466/Z/15/ZWellcome Trusthttp://dx.doi.org/10.13039/100010269
079605/Z/06/ZWellcome Trusthttp://dx.doi.org/10.13039/100010269
BB/L014211/1[BBSRC] Biotechnology and Biological Sciences Research Councilhttp://dx.doi.org/10.13039/501100000268

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