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Redox priming promotes Aurora A activation during mitosis

Lim, Daniel C. and Joukov, Vladimir and Rettenmaier, T. Justin and Kumagai, Akiko and Dunphy, William G. and Wells, James A. and Yaffe, Michael B. (2020) Redox priming promotes Aurora A activation during mitosis. Science Signaling, 13 (641). Art. No. eabb6707. ISSN 1945-0877. https://resolver.caltech.edu/CaltechAUTHORS:20200722-091504306

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Abstract

Cell cycle–dependent redox changes can mediate transient covalent modifications of cysteine thiols to modulate the activities of regulatory kinases and phosphatases. Our previously reported finding that protein cysteine oxidation is increased during mitosis relative to other cell cycle phases suggests that redox modifications could play prominent roles in regulating mitotic processes. The Aurora family of kinases and their downstream targets are key components of the cellular machinery that ensures the proper execution of mitosis and the accurate segregation of chromosomes to daughter cells. In this study, x-ray crystal structures of the Aurora A kinase domain delineate redox-sensitive cysteine residues that, upon covalent modification, can allosterically regulate kinase activity and oligomerization state. We showed in both Xenopus laevis egg extracts and mammalian cells that a conserved cysteine residue within the Aurora A activation loop is crucial for Aurora A activation by autophosphorylation. We further showed that covalent disulfide adducts of this residue promote autophosphorylation of the Aurora A kinase domain. These findings reveal a potential mechanistic link between Aurora A activation and changes in the intracellular redox state during mitosis and provide insights into how novel small-molecule inhibitors may be developed to target specific subpopulations of Aurora A.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1126/scisignal.abb6707DOIArticle
https://stke.sciencemag.org/content/suppl/2020/07/17/13.641.eabb6707.DC1PublisherSupplementary Materials
ftp://massive.ucsd.edu/MSV000085641Related ItemData
ORCID:
AuthorORCID
Lim, Daniel C.0000-0002-8861-4837
Joukov, Vladimir0000-0002-4721-209X
Kumagai, Akiko0000-0003-2422-8053
Dunphy, William G.0000-0001-7598-8939
Wells, James A.0000-0001-8267-5519
Yaffe, Michael B.0000-0002-9547-3251
Additional Information:© 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. This is an article distributed under the terms of the Science Journals Default License. Submitted 10 March 2020; Accepted 1 July 2020; Published 21 July 2020. We thank R. A. Grant, G. J. Dodge, and B. Imperiali (Massachusetts Institute of Technology) for assistance with shipping of the crystals and for help with the synchrotron data collection. We thank M. J. Eck and J. Genova (Dana-Farber Cancer Institute) for use of x-ray facilities and for assistance with data collection, J. C. Walter (Harvard Medical School) for providing laboratory facilities and advice, and B. Alhoch (California Institute of Technology) for assisting with the preparation of some of the Xenopus egg extract. We thank A. Koehler (Massachusetts Institute of Technology, Broad Institute of Harvard and MIT) and T. Lewis (Broad Institute of Harvard and MIT) for initiating the Aurora A inhibitor studies that led up to this work and H. Hayakawa and K. Munger (Brigham and Women’s Hospital and Harvard Medical School) for providing a human Aurora A cDNA construct. We would also like to thank J. Patterson, B. van de Kooij, B. Joughin, and P. Creixell (Yaffe laboratory, MIT) for helpful discussions. We thank the Koch Institute’s Robert A. Swanson (1969) Biotechnology Center for technical support, specifically G. Paradis, M. Jennings, M. Griffin, and M. Saturno-Condon (flow cytometry) and R. Cook, A. Leshinsky, and R. P. Schiavoni (biopolymers and proteomics). Funding: This work was supported by NIH grants R01-ES015339, R35-ES028374, R01-GM104047, and R21-ES020466 to M.B.Y., the Charles and Marjorie Holloway Foundation, and the MIT Center for Precision Cancer Medicine. This work was supported, in part, by the Koch Institute Support (core) grant P30-CA14051 from the National Cancer Institute. Support for this research was provided by a core center grant P30-ES002109 from the National Institute of Environmental Health Sciences, NIH. D.C.L. was also supported by a Merck-MIT Biology postdoctoral fellowship. Work from the Wells lab was supported by R01 CA191018. A.K. and W.G.D were supported by the NIH grant GM043974. This work is based on research conducted at the Northeastern Collaborative Access Team beamlines, which are funded by the National Institute of General Medical Sciences from the NIH (P30 GM124165). The Eiger 16M detector on 24-ID-E beam line is funded by a NIH-ORIP HEI grant (S10OD021527). This research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract no. DE-AC02-06CH11357. Author contributions: D.C.L., M.B.Y., V.J., T.J.R., and J.A.W. designed the experiments. D.C.L., V.J., A.K., and T.J.R. performed the experiments. D.C.L., M.B.Y., V.J., T.J.R., J.A.W., and W.G.D. performed the data processing, analysis, and interpretation. Competing interests: The authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper or the Supplementary Materials. The structures and x-ray data have been deposited to the PDB; accession codes are listed in table S2. The raw mass spectrometry data are deposited in the MassIVE repository as dataset MSV000085641 (ftp://massive.ucsd.edu/MSV000085641/).
Funders:
Funding AgencyGrant Number
NIHR01-ES015339
NIHR35-ES028374
NIHR01-GM104047
NIHR21-ES020466
Charles and Marjorie Holloway FoundationUNSPECIFIED
Massachusetts Institute of Technology (MIT)UNSPECIFIED
NIHP30-CA14051
NIHP30-ES002109
MerckUNSPECIFIED
NIHR01-CA191018
NIHGM043974
NIHP30 GM124165
NIHS10OD021527
Department of Energy (DOE)DE-AC02-06CH11357
National Cancer InstituteUNSPECIFIED
National Institute of Environmental Health SciencesUNSPECIFIED
Issue or Number:641
Record Number:CaltechAUTHORS:20200722-091504306
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200722-091504306
Official Citation:D. C. Lim, V. Joukov, T. J. Rettenmaier, A. Kumagai, W. G. Dunphy, J. A. Wells, M. B. Yaffe, Redox priming promotes Aurora A activation during mitosis. Sci. Signal. 13, eabb6707 (2020); DOI: 10.1126/scisignal.abb6707
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:104501
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:22 Jul 2020 16:28
Last Modified:22 Jul 2020 16:28

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