Meppelink Amanda, Kabeche Lilian, Vromans Martijn J M, Compton Duane A, Lens Susanne M A
Department of Medical Oncology, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands; Department of Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands.
Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA; Norris Cotton Cancer Center, Lebanon, NH 03756, USA.
Cell Rep. 2015 Apr 28;11(4):508-15. doi: 10.1016/j.celrep.2015.03.052. Epub 2015 Apr 16.
Correction of faulty kinetochore-microtubule attachments is essential for faithful chromosome segregation and dictated by the opposing activities of Aurora B kinase and PP1 and PP2A phosphatases. How kinase and phosphatase activities are appropriately balanced is less clear. Here, we show that a centromeric pool of PP2A-B56 counteracts Aurora B T-loop phosphorylation and is recruited to centromeres through Shugoshin-1 (Sgo1). In non-transformed RPE-1 cells, Aurora B, Sgo1, and PP2A-B56 are enriched on centromeres and levels diminish as chromosomes establish bi-oriented attachments. Elevating Sgo1 levels at centromeres recruits excess PP2A-B56, and this counteracts Aurora B kinase activity, undermining efficient correction of kinetochore-microtubule attachment errors. Conversely, Sgo1-depleted cells display reduced centromeric localization of Aurora B, whereas the remaining kinase is hyperactive due to concomitant reduction of centromeric PP2A-B56. Our data suggest that Sgo1 can tune the stability of kinetochore-microtubule attachments through recruitment of PP2A-B56 that balances Aurora B activity at the centromere.
纠正错误的动粒-微管附着对于准确的染色体分离至关重要，这由极光激酶B（Aurora B kinase）与蛋白磷酸酶1（PP1）和蛋白磷酸酶2A（PP2A）的相反活性所决定。激酶和磷酸酶活性如何适当平衡尚不清楚。在这里，我们表明PP2A-B56的着丝粒池可抵消极光激酶B的T环磷酸化，并通过守护蛋白1（Shugoshin-1，Sgo1）被招募到着丝粒。在未转化的视网膜色素上皮细胞（RPE-1细胞）中，极光激酶B、Sgo1和PP2A-B56在着丝粒上富集，随着染色体建立双定向附着，其水平降低。着丝粒处Sgo1水平升高会招募过量的PP2A-B56，这会抵消极光激酶B的活性，破坏动粒-微管附着错误的有效纠正。相反，Sgo1缺失的细胞显示极光激酶B在着丝粒的定位减少，而剩余的激酶由于着丝粒PP2A-B56的同时减少而过度活跃。我们的数据表明，Sgo1可以通过招募PP2A-B56来调节动粒-微管附着的稳定性，从而平衡着丝粒处的极光激酶B活性。
