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Aurora a Protein Kinase to the Centrosome and Beyond Laura Magnaghi-Jaulin, Grégory Eot-Houllier, Emmanuel Gallaud, Régis Giet

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Aurora a Protein Kinase to the Centrosome and Beyond Laura Magnaghi-Jaulin, Grégory Eot-Houllier, Emmanuel Gallaud, Régis Giet Aurora A Protein Kinase To the Centrosome and Beyond Laura Magnaghi-Jaulin, Grégory Eot-Houllier, Emmanuel Gallaud, Régis Giet To cite this version: Laura Magnaghi-Jaulin, Grégory Eot-Houllier, Emmanuel Gallaud, Régis Giet. Aurora A Pro- tein Kinase To the Centrosome and Beyond. Biomolecules, MDPI, 2019, 9 (1), pp.E28. 10.3390/biom9010028. hal-01993661 HAL Id: hal-01993661 https://hal-univ-rennes1.archives-ouvertes.fr/hal-01993661 Submitted on 4 Sep 2019 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. biomolecules Review Aurora A Protein Kinase: To the Centrosome and Beyond Laura Magnaghi-Jaulin, Grégory Eot-Houllier, Emmanuel Gallaud and Régis Giet * University of Rennes, CNRS UMR 6290, IGDR-Institute of Genetics and Development of Rennes, F-35000 Rennes, France; [email protected] (L.M.-J.); [email protected] (G.E.-H.); [email protected] (E.G.) * Correspondence: [email protected]; Tel.: +33-223234998 Received: 7 December 2018; Accepted: 9 January 2019; Published: 15 January 2019 Abstract: Accurate chromosome segregation requires the perfect spatiotemporal rearrangement of the cellular cytoskeleton. Isolated more than two decades ago from Drosophila, Aurora A is a widespread protein kinase that plays key roles during cell division. Numerous studies have described the localisation of Aurora A at centrosomes, the mitotic spindle, and, more recently, at mitotic centromeres. In this review, we will summarise the cytoskeletal rearrangements regulated by Aurora A during cell division. We will also discuss the recent discoveries showing that Aurora A also controls not only the dynamics of the cortical proteins but also regulates the centromeric proteins, revealing new roles for this kinase during cell division. Keywords: Aurora A protein kinase; centrosome; mitotic spindle; polarity; centromere; kinetochore; cohesion; transcription 1. Introduction Numerous mitotic events are controlled by phosphorylation signalling pathways. In general, extensive phosphorylation events orchestrate the entry into mitosis, whereas waves of dephosphorylation mark the exit [1]. The Aurora kinases are a family of serine/threonine kinases involved in cell-cycle progression, mostly during the G2 and M phases. The founding member of the family, increase in ploidy (IpI1), was isolated three decades ago from budding yeast through a genetic screen to find mutants required for chromosome segregation [2]. In higher eukaryotes, Aurora A was described in flies several years later, after screening a collection of female sterile mutants. Mutations in Aurora A lead to the formation of monopolar spindles in embryos and neural stem cells [3], similar in appearance to the aurora borealis. The name Aurora was then retained as the founding member of the family in higher eukaryotes. Yeast and starfish have one Aurora kinase [2,4,5]. Most animals have at least two and mammals have three Aurora A-like protein kinases, called Aurora A, B and C [6]. All members of this family, at varying degrees of strength, are involved in cancers and have therefore been subjected to the design of anti-cancer molecules [7,8]. Members of the family are evolutionarily conserved and likely share a common ancestor gene, suggested by the presence of a single Aurora gene in starfish [4]. During cell division, Aurora A and B localise to distinct subcellular structures of the mitotic apparatus. Aurora A is located on the duplicated centrosomes and the poles of the mitotic spindle [9–11]. Interestingly, it has also been shown to localise to centromeres during mitosis [12], as will be discussed in this review. Aurora B is part of a conserved protein complex (with three other proteins: Inner Centromere Protein (INCENP), Borealin, Survivin) called the chromosomal passenger complex (CPC). The CPC associates with centromeres during mitosis and re-localises to the central spindle and midbody during cytokinesis. Numerous Biomolecules 2019, 9, 28; doi:10.3390/biom9010028 www.mdpi.com/journal/biomolecules Biomolecules 2019, 9, 28 2 of 19 studies and reviews have described a clear role for Aurora B in controlling chromosome condensation, the correction of erroneous chromosome attachment to the mitotic spindle, and cytokinesis [13–15]. The function of Aurora C has remained unclear for a long time but recent studies have shown it is essentialBiomolecules for the 2019 control, 9, 28 of meiotic spindle assembly in mammalian oocytes [16,17].2 of In 19 addition, Aurora C prevents Aurora A from being incorporated into the CPC, a process essential to control Numerous studies and reviews have described a clear role for Aurora B in controlling chromosome meiotic spindlecondensation, length the [18 ].correction of erroneous chromosome attachment to the mitotic spindle, and Distinctcytokinesis polar and [13–15]. equatorial The function mitotic of Aurora functions C has remained have long unclear been for assigned a long time to but Aurora recent kinasesstudies A and B based on theirhave differentshown it is cellularessential for localisation the control [of6 ,meiotic19]. However, spindle assembly both enzymes in mammalian share oocytes major [16,17]. structural and sequence similarities.In addition, AuroraIn cellulo C prevents, their Aurora differential A from bein targetingg incorporated to distinct into the cellular CPC, a process structures essential is mediated to control meiotic spindle length [18]. by sequences outsideDistinct polar of their and equatorial catalytic mitotic domain, functions as Aurora have long kinase been assigned domains to Aurora can be kinases exchanged A and without affecting theirB based respective on their different localisation cellular or localisation function [6 [20,19].]. However, In addition, both theseenzymes two share kinases major structural have very similar phosphorylationand sequence sites insimilarities. vitro and In the cellulo use, their of specific differential Aurora targeting A and to Auroradistinct cellular B inhibitor structures associated is with phospho-proteomicmediated by studies sequences has outside proven of their that catalytic they sharedomain, identical as Aurora substrateskinase domains [21 can,22 be]. However,exchanged many of without affecting their respective localisation or function [20]. In addition, these two kinases have these Auroravery substratessimilar phosphorylation have not sites been in validatedvitro and thein use vivo of specificand it Aurora is still A notand Aurora clear ifB theseinhibitor targets are phosphorylatedassociated by Aurorawith phospho-proteomic A, Aurora B orstudies both. has Moreover, proven that the they timing share identical of these substrates phosphorylation [21,22]. events during cellHowever, division many remains of these elusive. Aurora substr Finally,ates theirhave not impact been validated on cell division,in vivo and byit ismutation still not clear analyses if has not been systematicallythese targets are investigated. phosphorylated Many by Aurora reviews A, Au haverora B already or both. focusedMoreover, on the the timing regulation of these of mitosis phosphorylation events during cell division remains elusive. Finally, their impact on cell division, by by Auroramutation kinase [analyses9,23]. Wehas will,not been therefore, systematically focus investigated. on functional Many reviews studies have of new already Aurora focused A on substrates, from entrythe into regulation mitosis of to mitosis metaphase/anaphase. by Aurora kinase [9,23]. In We particular, will, therefore, we willfocus highlighton functional Aurora studies Aof functions and substratesnew Aurora that participateA substrates, infrom the entry dynamics into mitosis of corticalto metaphase/anaphase. proteins, chromosome In particular, segregationwe will and centromere-relatedhighlight Aurora processes A functions (Figure and1). substrates that participate in the dynamics of cortical proteins, chromosome segregation and centromere-related processes (Figure 1). Figure 1. MajorFigure 1. substrates Major substrates of Aurora of Aurora A proteinA protein kinasekinase and and their their roles roles during during mitosis. mitosis. The area Theof area of influence ofinfluence Aurora of Aurora A protein A protein kinase kinase in thein the cell cell isis indicatedindicated in inlight light green. green. This area This includes area includesthe the cellular cortex, centrosomes and mitotic spindle. Note that a pool of Aurora A is also present at the cellular cortex,centromeres. centrosomes MT: microtubule. and mitotic spindle. Note that a pool of Aurora A is also present at the centromeres. MT: microtubule. 2. Aurora A Regulates Centrosome Maturation, Centrosome Integrity and Centrosomal Microtubule Polymerisation Interference with Aurora A by different methods all lead to mitotic spindle assembly defects, ranging from monopolar spindles, with apparently unseparated centrosomes, to bipolar spindles Biomolecules 2019, 9, 28 3 of 19 with shorter mitotic spindles. The location of the kinase on the centrosome led to the conclusion
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