Phosphorylation of Merlin by Aurora A kinase appears necessary for mitotic progression
Résumé
Although Merlin function as a tumor suppressor and regulator of mitogenic signaling networks such as the Ras/rac, Akt or Hippo pathways is well documented,in mammals as well as in insects, its role during cell cycle progression remains unclear. In this study, using a combination of approaches, including FACS analysis, time-lapse imaging, immunofluorescence microscopy and co-immunoprecipitation, we show that Ser-518 of Merlin is a substrate of the Aurora A kinase during mitosis and that its phosphorylation facilitates the phosphorylation of a newly discovered site, Thr-581. We found that the expression in Hela cells of a Merlin variant that is phosphorylation-defective on both sites leads to a defect in centrosomes and mitotic spindles positioning during metaphase and delays the transition from metaphase to anaphase. We also show that the dual mitotic phosphorylation not only reduces Merlin binding to microtubules but also timely modulates Ezrin interaction with the cytoskeleton. Finally, we identify several point mutants of Merlin associated with Neurofibromatosis type 2 that display an aberant phosphorylation profile along with defective α-tubulin binding properties. Altogether, our findings of an Aurora A-mediated interaction of Merlin with α-tubulin and Ezrin suggest a potential role for Merlin in cell cycle progression.
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