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: Limiting titration of the specific Plk1 inhibitor BI2356 revealed a synthetic interaction with Mio depletion. In Mio-depleted cells, lower concentrations of BI2536 caused a synergistic increase in the percentage of cells with monopolar spindles relative to the same drug treatment of control RNAi cells (Fig. 5, A–C). Thus, cells depleted of Mio assembled monopolar spindles at concentrations of the drug that did not appreciably affect cells after the control RNAi. This was seen most clearly in Fig. 5 B, which plots Δ, the difference in the percentage of monopolar spindles after drug treatments with or without Mio RNAi. A positive slope of Δ indicates a synthetic response, whereas a horizontal line indicates no increase in drug sensitivity after Mio RNAi. It is important to note that after an initial strong synthetic response, the Δ curve for Plk1 inhibition decreases because both the control and Mio-depleted samples are approaching a limit of 90% monopolar cells.
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.