Mio depletion links mTOR regulation to Aurora A and Plk1 activation at mitotic centrosomes.
Bottom Line: In this study, we report that Mio, a highly conserved member of the SEACAT/GATOR2 complex necessary for the activation of mTORC1 kinase, plays a critical role in mitotic spindle formation and subsequent chromosome segregation by regulating the proper concentration of active key mitotic kinases Plk1 and Aurora A at centrosomes and spindle poles.Mio-depleted cells showed reduced activation of Plk1 and Aurora A kinase at spindle poles and an impaired localization of MCAK and HURP, two key regulators of mitotic spindle formation and known substrates of Aurora A kinase, resulting in spindle assembly and cytokinesis defects.Our results indicate that a major function of Mio in mitosis is to regulate the activation/deactivation of Plk1 and Aurora A, possibly by linking them to mTOR signaling in a pathway to promote faithful mitotic progression.
Affiliation: Wellcome Trust Centre for Cell Biology, Institute of Cell Biology, University of Edinburgh, Edinburgh EH9 3BF, Scotland, UK email@example.com Bill.Earnshaw@ed.ac.uk.Show MeSH
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Mentions: Mio is a highly conserved member of the SEACAT/GATOR2 complex, antagonizing GATOR1, a known inhibitor of Rag-1 GTPase, and hence promoting mTOR signaling (Bar-Peled et al., 2013; Panchaud et al., 2013a). We therefore decided to look directly at levels of active mTOR in cells after Mio depletion. Upon its activation, mTOR is phosphorylated on several sites, including Ser2481 (Peterson et al., 2000). mTOR Ser2481 autophosphorylation correlates with mTOR catalytic activity (Soliman et al., 2010). Although levels of total mTOR appeared unaffected by Mio depletion (Fig. 9 C), levels of active mTOR (mTORS2481ph) on centrosomes and spindles were much lower in Mio-depleted cells than in control RNAi cells (Fig. 9, A and B).
Affiliation: Wellcome Trust Centre for Cell Biology, Institute of Cell Biology, University of Edinburgh, Edinburgh EH9 3BF, Scotland, UK firstname.lastname@example.org Bill.Earnshaw@ed.ac.uk.