Knowlton Anne Lide, Lan Weijie, Stukenberg P Todd
Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, Virginia 22908, USA.
Curr Biol. 2006 Sep 5;16(17):1705-10. doi: 10.1016/j.cub.2006.07.057.
Kinetochores often form merotelic attachments, in which a single kinetochore is attached to microtubules from both spindle poles. These attachments can result in improper chromosome segregation and are a significant source of aneuploidy, a hallmark of cancer. Aurora B kinase and the kinesin-13 microtubule depolymerase mitotic-centromere-associated kinesin (MCAK) are required to release improper microtubule attachments. Aurora B regulates MCAK's activity and localization. We set out to understand why MCAK and Aurora B are more abundant at some metaphase-aligned centromeres but are present at low amounts on most others. We found that members of the Aurora B complex are specifically enriched at merotelic attachment sites. We also found that Aurora B does not require its activity to become enriched at these sites; however, inhibition of Aurora B activity causes a significant increase in the number of merotelic attachments per cell. Aurora B activity enriches MCAK at merotelic attachments and phosphorylates MCAK on residues that regulate its microtubule depolymerase activity. These data demonstrate that proteins that resolve the defect are specifically localized to merotelic attachments, where their enzymatic activities are regulated.
动粒常常形成着丝粒外侧连接，即单个动粒与来自纺锤体两极的微管相连。这些连接会导致染色体分离异常，是非整倍体的一个重要来源，而非整倍体是癌症的一个标志。Aurora B激酶和驱动蛋白-13微管解聚酶有丝分裂着丝粒相关驱动蛋白（MCAK）是释放异常微管连接所必需的。Aurora B调节MCAK的活性和定位。我们着手探究为什么MCAK和Aurora B在一些中期排列的着丝粒处含量更高，而在大多数其他着丝粒处含量较低。我们发现Aurora B复合体的成员在着丝粒外侧连接位点特异性富集。我们还发现Aurora B不需要其活性就能在这些位点富集；然而，抑制Aurora B活性会导致每个细胞中着丝粒外侧连接的数量显著增加。Aurora B活性在着丝粒外侧连接处富集MCAK，并使MCAK上调节其微管解聚酶活性的残基磷酸化。这些数据表明，解决缺陷的蛋白质特异性定位于着丝粒外侧连接，在那里它们的酶活性受到调节。
