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A rapid computational approach identifies SPICE1 as an Aurora kinase substrate

Aurora kinases play a major role in mitosis by regulating diverse substrates. Defining their critical downstream targets is important in understanding Aurora kinase function. Here we have developed an unbiased computational approach to identify new Aurora kinase substrates based on phosphorylation s...

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Detalles Bibliográficos
Autores principales: Deretic, Jovana, Kerr, Alastair, Welburn, Julie P. I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589576/
https://www.ncbi.nlm.nih.gov/pubmed/30485161
http://dx.doi.org/10.1091/mbc.E18-08-0495
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author Deretic, Jovana
Kerr, Alastair
Welburn, Julie P. I.
author_facet Deretic, Jovana
Kerr, Alastair
Welburn, Julie P. I.
author_sort Deretic, Jovana
collection PubMed
description Aurora kinases play a major role in mitosis by regulating diverse substrates. Defining their critical downstream targets is important in understanding Aurora kinase function. Here we have developed an unbiased computational approach to identify new Aurora kinase substrates based on phosphorylation site clustering, protein localization, protein structure, and species conservation. We validate the microtubule-associated proteins Clasp2, Elys, tubulin tyrosine ligase-like polyglutamylase residues 330–624 and spindle and centriole associated protein 1, residues 549–855 (SPICE1), as Aurora A and B kinases substrates in vitro. We also demonstrate that SPICE1 localization is regulated by Aurora kinases during mitosis. In the absence of Aurora kinase activity, SPICE1 remains at centrioles but does not target to the spindle. Similarly, a nonphosphorylatable SPICE1 mutant no longer localizes to the spindle. Finally, we show that misregulating SPICE1 phosphorylation results in abnormal centriole number, spindle multipolarity, and chromosome alignment defects. Overall, our work indicates that temporal and spatial Aurora kinase–mediated regulation of SPICE1 is important for correct chromosome segregation. In addition, our work provides a database-search tool that enables rapid identification of Aurora kinase substrates.
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spelling pubmed-65895762019-06-28 A rapid computational approach identifies SPICE1 as an Aurora kinase substrate Deretic, Jovana Kerr, Alastair Welburn, Julie P. I. Mol Biol Cell Brief Reports Aurora kinases play a major role in mitosis by regulating diverse substrates. Defining their critical downstream targets is important in understanding Aurora kinase function. Here we have developed an unbiased computational approach to identify new Aurora kinase substrates based on phosphorylation site clustering, protein localization, protein structure, and species conservation. We validate the microtubule-associated proteins Clasp2, Elys, tubulin tyrosine ligase-like polyglutamylase residues 330–624 and spindle and centriole associated protein 1, residues 549–855 (SPICE1), as Aurora A and B kinases substrates in vitro. We also demonstrate that SPICE1 localization is regulated by Aurora kinases during mitosis. In the absence of Aurora kinase activity, SPICE1 remains at centrioles but does not target to the spindle. Similarly, a nonphosphorylatable SPICE1 mutant no longer localizes to the spindle. Finally, we show that misregulating SPICE1 phosphorylation results in abnormal centriole number, spindle multipolarity, and chromosome alignment defects. Overall, our work indicates that temporal and spatial Aurora kinase–mediated regulation of SPICE1 is important for correct chromosome segregation. In addition, our work provides a database-search tool that enables rapid identification of Aurora kinase substrates. The American Society for Cell Biology 2019-02-01 /pmc/articles/PMC6589576/ /pubmed/30485161 http://dx.doi.org/10.1091/mbc.E18-08-0495 Text en © 2019 Deretic et al. “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology. http://creativecommons.org/licenses/by-nc-sa/3.0 This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License.
spellingShingle Brief Reports
Deretic, Jovana
Kerr, Alastair
Welburn, Julie P. I.
A rapid computational approach identifies SPICE1 as an Aurora kinase substrate
title A rapid computational approach identifies SPICE1 as an Aurora kinase substrate
title_full A rapid computational approach identifies SPICE1 as an Aurora kinase substrate
title_fullStr A rapid computational approach identifies SPICE1 as an Aurora kinase substrate
title_full_unstemmed A rapid computational approach identifies SPICE1 as an Aurora kinase substrate
title_short A rapid computational approach identifies SPICE1 as an Aurora kinase substrate
title_sort rapid computational approach identifies spice1 as an aurora kinase substrate
topic Brief Reports
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589576/
https://www.ncbi.nlm.nih.gov/pubmed/30485161
http://dx.doi.org/10.1091/mbc.E18-08-0495
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