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Constitutive regulation of mitochondrial morphology by Aurora A kinase depends on a predicted cryptic targeting sequence at the N-terminus

Grant, Rhys and Abdelbaki, Ahmed and Bertoldi, Alessia and Gavilan, Maria P. and Mansfeld, Jörg and Glover, David M. and Lindon, Catherine (2018) Constitutive regulation of mitochondrial morphology by Aurora A kinase depends on a predicted cryptic targeting sequence at the N-terminus. Open Biology, 8 (6). Art. No. 170272. ISSN 2046-2441. PMCID PMC6030116. https://resolver.caltech.edu/CaltechAUTHORS:20200807-114540635

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Abstract

Aurora A kinase (AURKA) is a major regulator of mitosis and an important driver of cancer progression. The roles of AURKA outside of mitosis, and how these might contribute to cancer progression, are not well understood. Here, we show that a fraction of cytoplasmic AURKA is associated with mitochondria, co-fractionating in cell extracts and interacting with mitochondrial proteins by reciprocal co-immunoprecipitation. We have also found that the dynamics of the mitochondrial network are sensitive to AURKA inhibition, depletion or overexpression. This can account for the different mitochondrial morphologies observed in RPE-1 and U2OS cell lines, which show very different levels of expression of AURKA. We identify the mitochondrial fraction of AURKA as influencing mitochondrial morphology, because an N-terminally truncated version of the kinase that does not localize to mitochondria does not affect the mitochondrial network. We identify a cryptic mitochondrial targeting sequence in the AURKA N-terminus and discuss how alternative conformations of the protein may influence its cytoplasmic fate.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1098/rsob.170272DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6030116/PubMed CentralArticle
ORCID:
AuthorORCID
Grant, Rhys0000-0003-4027-0972
Abdelbaki, Ahmed0000-0002-9151-3113
Bertoldi, Alessia0000-0002-5929-2269
Gavilan, Maria P.0000-0003-3694-8525
Mansfeld, Jörg0000-0002-0562-8206
Glover, David M.0000-0003-0956-0103
Lindon, Catherine0000-0003-3554-2574
Additional Information:© 2018 The Authors. Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited. Received: 22 December 2017. Accepted: 18 May 2018. Our thanks go to Helfrid Hochegger for sharing unpublished results, to David Nelson and Heike Laman for sharing protocols, to Jonathon Pines and Paola Marcos Casanova for help in generating the endogenous AURKA-mVenus knock-in, to Steve Royle for mCherry-MitoTrap, to Mingwei Min and Santiago Caño-Muñiz for help with data analysis, and to Chris Connor and Begum Akman for practical assistance. This work was supported through funding to C.L. from Cancer Research UK (C3/A10239), Medical Research Council (MR/M01102X/1) and the Department of Genetics. D.M.G. received support from Cancer Research UK (C3/A18795). R.G. was supported by a PhD studentship from the MRC and additional funding from the Department of Genetics, Cambridge Philosophical Society, Crane's Charity and DRC. A.M.A. is the recipient of a Yousef Jameel Scholarship from the Cambridge International Trust. A.B. received an Erasmus placement (European Commission Lifelong Learning programme) and M.P.G. was supported by Consolider (CSD2009-00016) and Ministerio de Ciencia e Innovación, Spain, through JdC and Jose Castillejo programmes. J.M. is supported by the German Research Foundation (DFG) (Emmy Noether; MA 5831/1-1) and receives funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant agreement no. 680042). Authors' contributions: R.G. carried out data acquisition and analysis and prepared figures. A.M.A. and A.B. contributed specific experiments. M.P.G. generated the RPE-1 FRT/TO AURKA-Venus line, while J.M. generated endogenously tagged AURKA-mVenus. The project was conceived by C.L. and D.M.G. and directed by C.L. R.G., J.M., D.M.G. and C.L. all contributed to the writing and reviewing of the manuscript. All the authors gave their final approval for publication. We declare we have no competing interests.
Funders:
Funding AgencyGrant Number
Cancer Research UKC3/A10239
Medical Research Council (UK)MR/M01102X/1
University of CambridgeUNSPECIFIED
Cancer Research UKC3/A18795
Cambridge Philosophical SocietyUNSPECIFIED
Crane's CharityUNSPECIFIED
Cambridge International TrustUNSPECIFIED
Ministerio de Ciencia e Innovación (MCINN) CSD2009-00016
Deutsche Forschungsgemeinschaft (DFG)MA 5831/1-1
European Research Council (ERC)680042
Issue or Number:6
PubMed Central ID:PMC6030116
Record Number:CaltechAUTHORS:20200807-114540635
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20200807-114540635
Official Citation:Grant R, Abdelbaki A, Bertoldi A, et al. Constitutive regulation of mitochondrial morphology by Aurora A kinase depends on a predicted cryptic targeting sequence at the N-terminus. Open Biol. 2018;8(6):170272. doi:10.1098/rsob.170272
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:104825
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:10 Aug 2020 14:25
Last Modified:10 Aug 2020 14:25

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