Proteomic study identifies Aurora-A-mediated regulation of alternative splicing through multiple splicing factors

The cell cycle regulator Aurora-A kinase presents an attractive target for cancer therapies, though its inhibition is also associated with toxic side effects. To gain a more nuanced understanding of Aurora-A function, we applied shotgun proteomics to identify 407 specific protein partners, including...

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Authors: Damodaran, Arun Prasath, Gavard, Olivia, Gagné, Jean-Philippe, Rogalska, Malgorzata, Behera, Amit K., Mancini, Estefanía, Bertolin, Giulia, Courthéoux, Thibault, Kumari, Bandana, Cailloce, Justine, Méreau, Agnès, Poirier, Guy G., Valcárcel, J. (Juan), Gonatopoulos-Pournatzis, Thomas, Watrin, Erwan, Prigent, Claude
Format: article
Status:Published version
Publication Date:2024
Country:España
Institution:Universitat Pompeu Fabra
Repository:Repositorio Digital de la UPF
OAI Identifier:oai:repositori.upf.edu:10230/69523
Online Access:http://hdl.handle.net/10230/69523
http://dx.doi.org/10.1016/j.jbc.2024.108000
Access Level:Open access
Keyword:Aurora-A
CLK1
RNA
SR protein
Cancer
Cell cycle
hnRNP proteins
Kinase
Mitosis
Proteomics
Splicing
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spelling Proteomic study identifies Aurora-A-mediated regulation of alternative splicing through multiple splicing factorsDamodaran, Arun PrasathGavard, OliviaGagné, Jean-PhilippeRogalska, MalgorzataBehera, Amit K.Mancini, EstefaníaBertolin, GiuliaCourthéoux, ThibaultKumari, BandanaCailloce, JustineMéreau, AgnèsPoirier, Guy G.Valcárcel, J. (Juan)Gonatopoulos-Pournatzis, ThomasWatrin, ErwanPrigent, ClaudeAurora-ACLK1RNASR proteinCancerCell cyclehnRNP proteinsKinaseMitosisProteomicsSplicingThe cell cycle regulator Aurora-A kinase presents an attractive target for cancer therapies, though its inhibition is also associated with toxic side effects. To gain a more nuanced understanding of Aurora-A function, we applied shotgun proteomics to identify 407 specific protein partners, including several splicing factors. Supporting a role in alternative splicing, we found that Aurora-A localizes to nuclear speckles, the storehouse of splicing proteins. Aurora-A interacts with and phosphorylates splicing factors both in vitro and in vivo, suggesting that it regulates alternative splicing by modulating the activity of these splicing factors. Consistently, Aurora-A inhibition significantly impacts the alternative splicing of 505 genes, with RNA motif analysis revealing an enrichment for Aurora-A interacting splicing factors. Additionally, we observed a significant positive correlation between the splicing events regulated by Aurora-A and those modulated by its interacting splicing factors. An interesting example is represented by CLK1 exon 4, which appears to be regulated by Aurora-A through SRSF3. Collectively, our findings highlight a broad role of Aurora-A in the regulation of alternative splicing.Work by C. P.'s team is supported by the University of Rennes 1, the CNRS, and the Ligue Nationale Contre le Cancer “Équipe labellisée 2014-2017” and ligue35. The PhD salary of A. P. D. and the post-doc salary of T. C are supported by the Ligue Nationale Contre le Cancer and the Bretagne region. This work is also supported by the NCI/NIH Intramural Research Program (Project ZIABC012019). Work in J. V. lab was supported by Spanish Ministry of Science and Innovation (PID2020-114630GB-100/AEI/10.13039/501100011033), EMBL Partnership and Severo Ochoa Centre of Excellence (CEX2020-001049-S, MCIN/AEI/10.13039/501100011033), and the Generalitat de Catalunya through the CERCA programme.Elsevier202520252024info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttp://hdl.handle.net/10230/69523http://dx.doi.org/10.1016/j.jbc.2024.108000reponame:Repositorio Digital de la UPFinstname:Universitat Pompeu FabraInglésJ Biol Chem. 2024 Nov 17;301(1):108000info:eu-repo/grantAgreement/ES/2PE/PID2020-114630GB-100info:eu-repo/grantAgreement/ES/2PE/CEX2020-001049-S© 2024 THE AUTHORS. Published by Elsevier Inc on behalf of American Society for Biochemistry and Molecular Biology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).http://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:repositori.upf.edu:10230/695232026-06-12T07:21:37Z
dc.title.none.fl_str_mv Proteomic study identifies Aurora-A-mediated regulation of alternative splicing through multiple splicing factors
title Proteomic study identifies Aurora-A-mediated regulation of alternative splicing through multiple splicing factors
spellingShingle Proteomic study identifies Aurora-A-mediated regulation of alternative splicing through multiple splicing factors
Damodaran, Arun Prasath
Aurora-A
CLK1
RNA
SR protein
Cancer
Cell cycle
hnRNP proteins
Kinase
Mitosis
Proteomics
Splicing
title_short Proteomic study identifies Aurora-A-mediated regulation of alternative splicing through multiple splicing factors
title_full Proteomic study identifies Aurora-A-mediated regulation of alternative splicing through multiple splicing factors
title_fullStr Proteomic study identifies Aurora-A-mediated regulation of alternative splicing through multiple splicing factors
title_full_unstemmed Proteomic study identifies Aurora-A-mediated regulation of alternative splicing through multiple splicing factors
title_sort Proteomic study identifies Aurora-A-mediated regulation of alternative splicing through multiple splicing factors
dc.creator.none.fl_str_mv Damodaran, Arun Prasath
Gavard, Olivia
Gagné, Jean-Philippe
Rogalska, Malgorzata
Behera, Amit K.
Mancini, Estefanía
Bertolin, Giulia
Courthéoux, Thibault
Kumari, Bandana
Cailloce, Justine
Méreau, Agnès
Poirier, Guy G.
Valcárcel, J. (Juan)
Gonatopoulos-Pournatzis, Thomas
Watrin, Erwan
Prigent, Claude
author Damodaran, Arun Prasath
author_facet Damodaran, Arun Prasath
Gavard, Olivia
Gagné, Jean-Philippe
Rogalska, Malgorzata
Behera, Amit K.
Mancini, Estefanía
Bertolin, Giulia
Courthéoux, Thibault
Kumari, Bandana
Cailloce, Justine
Méreau, Agnès
Poirier, Guy G.
Valcárcel, J. (Juan)
Gonatopoulos-Pournatzis, Thomas
Watrin, Erwan
Prigent, Claude
author_role author
author2 Gavard, Olivia
Gagné, Jean-Philippe
Rogalska, Malgorzata
Behera, Amit K.
Mancini, Estefanía
Bertolin, Giulia
Courthéoux, Thibault
Kumari, Bandana
Cailloce, Justine
Méreau, Agnès
Poirier, Guy G.
Valcárcel, J. (Juan)
Gonatopoulos-Pournatzis, Thomas
Watrin, Erwan
Prigent, Claude
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Aurora-A
CLK1
RNA
SR protein
Cancer
Cell cycle
hnRNP proteins
Kinase
Mitosis
Proteomics
Splicing
topic Aurora-A
CLK1
RNA
SR protein
Cancer
Cell cycle
hnRNP proteins
Kinase
Mitosis
Proteomics
Splicing
description The cell cycle regulator Aurora-A kinase presents an attractive target for cancer therapies, though its inhibition is also associated with toxic side effects. To gain a more nuanced understanding of Aurora-A function, we applied shotgun proteomics to identify 407 specific protein partners, including several splicing factors. Supporting a role in alternative splicing, we found that Aurora-A localizes to nuclear speckles, the storehouse of splicing proteins. Aurora-A interacts with and phosphorylates splicing factors both in vitro and in vivo, suggesting that it regulates alternative splicing by modulating the activity of these splicing factors. Consistently, Aurora-A inhibition significantly impacts the alternative splicing of 505 genes, with RNA motif analysis revealing an enrichment for Aurora-A interacting splicing factors. Additionally, we observed a significant positive correlation between the splicing events regulated by Aurora-A and those modulated by its interacting splicing factors. An interesting example is represented by CLK1 exon 4, which appears to be regulated by Aurora-A through SRSF3. Collectively, our findings highlight a broad role of Aurora-A in the regulation of alternative splicing.
publishDate 2024
dc.date.none.fl_str_mv 2024
2025
2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10230/69523
http://dx.doi.org/10.1016/j.jbc.2024.108000
url http://hdl.handle.net/10230/69523
http://dx.doi.org/10.1016/j.jbc.2024.108000
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv J Biol Chem. 2024 Nov 17;301(1):108000
info:eu-repo/grantAgreement/ES/2PE/PID2020-114630GB-100
info:eu-repo/grantAgreement/ES/2PE/CEX2020-001049-S
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by-nc-nd/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:Repositorio Digital de la UPF
instname:Universitat Pompeu Fabra
instname_str Universitat Pompeu Fabra
reponame_str Repositorio Digital de la UPF
collection Repositorio Digital de la UPF
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15.811543

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