journal.pgen.1005345.pdf (8.07 MB)
Aurora-A-dependent control of TACC3 influences the rate of mitotic spindle assembly
journal contributionposted on 2015-06-22, 14:13 authored by Selena G. Burgess, I. Peset, N. Joseph, T. Cavazza, I. Vernos, M. Pfuhl, F. Gergely, Richard Bayliss
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 microtubulecrosslinking 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.
: This work was funded by: Cancer Research UK (C24461/A12772 to RB and C14303/ A17197 to FG) http://www.cancerresearchuk.org Medical Research Council (G0800021) to RB http:// www.mrc.ac.uk Royal Society University Research Fellowships to FG and RB. http://www.royalsoc.ac.uk University of Cambridge to FG http://www.cam.ac.uk Hutchison-Whampoa to FG http://www.hutchisonwhampoa.com/en/media/press_each.php?id=2025 Spanish Ministry of Economy and Competitiveness (BFU2009-10202 and BFU2012-37163) to IV and (BES-2010-031355) to TC and ('Centro de Excelencia Severo Ochoa 2013-2017', SEV-2012- 0208) to the CRG
CitationPLoS Genetics 11(7): e1005345.
Author affiliation/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Biological Sciences/Department of Biochemistry
- VoR (Version of Record)