Aurora-A-Dependent Control of TACC3 Influences the Rate of Mitotic Spindle Assembly.
The essential mammalian gene TACC3 is frequently mutated and amplified in cancers and its fusion products exhibit oncogenic activity in glioblastomas. TACC3 functions in mitotic spindle assembly and chromosome segregation. In particular, phosphorylation on S558 by the mitotic kinase, Aurora-A, promo...
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Public Library of Science (PLoS)
2015-07-01
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| Series: | PLoS Genetics |
| Online Access: | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1005345&type=printable |
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| author | Selena G Burgess Isabel Peset Nimesh Joseph Tommaso Cavazza Isabelle Vernos Mark Pfuhl Fanni Gergely Richard Bayliss |
| author_facet | Selena G Burgess Isabel Peset Nimesh Joseph Tommaso Cavazza Isabelle Vernos Mark Pfuhl Fanni Gergely Richard Bayliss |
| author_sort | Selena G Burgess |
| collection | DOAJ |
| description | The essential mammalian gene TACC3 is frequently mutated and amplified in cancers and its fusion products exhibit oncogenic activity in glioblastomas. TACC3 functions in mitotic spindle assembly and chromosome segregation. In particular, phosphorylation on S558 by the mitotic kinase, Aurora-A, promotes spindle recruitment of TACC3 and triggers the formation of a complex with ch-TOG-clathrin that crosslinks and stabilises kinetochore microtubules. Here we map the Aurora-A-binding interface in TACC3 and show that TACC3 potently activates Aurora-A through a domain centered on F525. Vertebrate cells carrying homozygous F525A mutation in the endogenous TACC3 loci exhibit defects in TACC3 function, namely perturbed localization, reduced phosphorylation and weakened interaction with clathrin. The most striking feature of the F525A cells however is a marked shortening of mitosis, at least in part due to rapid spindle assembly. F525A cells do not exhibit chromosome missegregation, indicating that they undergo fast yet apparently faithful mitosis. By contrast, mutating the phosphorylation site S558 to alanine in TACC3 causes aneuploidy without a significant change in mitotic duration. Our work has therefore defined a regulatory role for the Aurora-A-TACC3 interaction beyond the act of phosphorylation at S558. We propose that the regulatory relationship between Aurora-A and TACC3 enables the transition from the microtubule-polymerase activity of TACC3-ch-TOG to the microtubule-crosslinking activity of TACC3-ch-TOG-clathrin complexes as mitosis progresses. Aurora-A-dependent control of TACC3 could determine the balance between these activities, thereby influencing not only spindle length and stability but also the speed of spindle formation with vital consequences for chromosome alignment and segregation. |
| format | Article |
| id | doaj-art-b5677532a490461bba5d2a583ccf56d7 |
| institution | OA Journals |
| issn | 1553-7390 1553-7404 |
| language | English |
| publishDate | 2015-07-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Genetics |
| spelling | doaj-art-b5677532a490461bba5d2a583ccf56d72025-08-20T02:22:40ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042015-07-01117e100534510.1371/journal.pgen.1005345Aurora-A-Dependent Control of TACC3 Influences the Rate of Mitotic Spindle Assembly.Selena G BurgessIsabel PesetNimesh JosephTommaso CavazzaIsabelle VernosMark PfuhlFanni GergelyRichard BaylissThe essential mammalian gene TACC3 is frequently mutated and amplified in cancers and its fusion products exhibit oncogenic activity in glioblastomas. TACC3 functions in mitotic spindle assembly and chromosome segregation. In particular, phosphorylation on S558 by the mitotic kinase, Aurora-A, promotes spindle recruitment of TACC3 and triggers the formation of a complex with ch-TOG-clathrin that crosslinks and stabilises kinetochore microtubules. Here we map the Aurora-A-binding interface in TACC3 and show that TACC3 potently activates Aurora-A through a domain centered on F525. Vertebrate cells carrying homozygous F525A mutation in the endogenous TACC3 loci exhibit defects in TACC3 function, namely perturbed localization, reduced phosphorylation and weakened interaction with clathrin. The most striking feature of the F525A cells however is a marked shortening of mitosis, at least in part due to rapid spindle assembly. F525A cells do not exhibit chromosome missegregation, indicating that they undergo fast yet apparently faithful mitosis. By contrast, mutating the phosphorylation site S558 to alanine in TACC3 causes aneuploidy without a significant change in mitotic duration. Our work has therefore defined a regulatory role for the Aurora-A-TACC3 interaction beyond the act of phosphorylation at S558. We propose that the regulatory relationship between Aurora-A and TACC3 enables the transition from the microtubule-polymerase activity of TACC3-ch-TOG to the microtubule-crosslinking activity of TACC3-ch-TOG-clathrin complexes as mitosis progresses. Aurora-A-dependent control of TACC3 could determine the balance between these activities, thereby influencing not only spindle length and stability but also the speed of spindle formation with vital consequences for chromosome alignment and segregation.https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1005345&type=printable |
| spellingShingle | Selena G Burgess Isabel Peset Nimesh Joseph Tommaso Cavazza Isabelle Vernos Mark Pfuhl Fanni Gergely Richard Bayliss Aurora-A-Dependent Control of TACC3 Influences the Rate of Mitotic Spindle Assembly. PLoS Genetics |
| title | Aurora-A-Dependent Control of TACC3 Influences the Rate of Mitotic Spindle Assembly. |
| title_full | Aurora-A-Dependent Control of TACC3 Influences the Rate of Mitotic Spindle Assembly. |
| title_fullStr | Aurora-A-Dependent Control of TACC3 Influences the Rate of Mitotic Spindle Assembly. |
| title_full_unstemmed | Aurora-A-Dependent Control of TACC3 Influences the Rate of Mitotic Spindle Assembly. |
| title_short | Aurora-A-Dependent Control of TACC3 Influences the Rate of Mitotic Spindle Assembly. |
| title_sort | aurora a dependent control of tacc3 influences the rate of mitotic spindle assembly |
| url | https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1005345&type=printable |
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