Joseph Jomon, Liu Song-Tao, Jablonski Sandra A, Yen Tim J, Dasso Mary
National Institutes of Health, National Institute of Child Health and Human Development, Building 18, Room 106, 18 Library Drive, MSC-5431, Bethesda, MD 20892, USA.
Curr Biol. 2004 Apr 6;14(7):611-7. doi: 10.1016/j.cub.2004.03.031.
RanGAP1 is the activating protein for the Ran GTPase. Vertebrate RanGAP1 is conjugated to a small ubiquitin-like protein, SUMO-1. This modification promotes association of RanGAP1 with the interphase nuclear pore complex (NPC) through binding to the nucleoporin RanBP2, also known as Nup358. During mitosis, RanGAP1 is concentrated at kinetochores in a microtubule- (MT) and SUMO-1-dependent fashion. RanBP2 is also abundantly found on kinetochores in mitosis. Here we show that ablation of proteins required for MT-kinetochore attachment (Hec1/Ndc80, Nuf2 ) disrupts RanGAP1 and RanBP2 targeting to kinetochores. No similar disruption was observed after ablation of proteins nonessential for MT-kinetochore interactions (CENP-I, Bub1, CENP-E ). Acquisition of RanGAP1 and RanBP2 by kinetochores is temporally correlated in untreated cells with MT attachment. These patterns of accumulation suggest a loading mechanism wherein the RanGAP1-RanBP2 complex may be transferred along the MT onto the kinetochore. Depletion of RanBP2 caused mislocalization of RanGAP1, Mad1, Mad2, CENP-E, and CENP-F, as well as loss of cold-stable kinetochore-MT interactions and accumulation of mitotic cells with multipolar spindles and unaligned chromosomes. Taken together, our observations indicate that RanBP2 and RanGAP1 are targeted as a single complex that is both regulated by and essential for stable kinetochore-MT association.
RanGAP1是Ran GTP酶的激活蛋白。脊椎动物的RanGAP1与一种小的类泛素蛋白SUMO-1结合。这种修饰通过与核孔蛋白RanBP2(也称为Nup358)结合,促进RanGAP1与间期核孔复合体(NPC)的结合。在有丝分裂期间,RanGAP1以微管(MT)和SUMO-1依赖的方式集中在动粒上。RanBP2在有丝分裂的动粒上也大量存在。在这里,我们表明,MT-动粒附着所需蛋白质(Hec1/Ndc80、Nuf2)的缺失会破坏RanGAP1和RanBP2定位于动粒。在缺失对MT-动粒相互作用不必要的蛋白质(CENP-I、Bub1、CENP-E)后,未观察到类似的破坏。在未处理的细胞中,动粒获得RanGAP1和RanBP2与MT附着在时间上相关。这些积累模式表明一种加载机制,其中RanGAP1-RanBP2复合物可能沿着MT转移到动粒上。RanBP2的缺失导致RanGAP1、Mad1、Mad2、CENP-E和CENP-F的定位错误,以及冷稳定的动粒-MT相互作用的丧失,以及有丝分裂细胞中多极纺锤体和染色体未对齐的积累。综上所述,我们的观察结果表明,RanBP2和RanGAP1作为一个单一的复合物被靶向,该复合物既受稳定的动粒-MT关联调节,又对其至关重要。