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RanGTP梯度——有丝分裂纺锤体的“全球定位系统” 。

The RanGTP gradient - a GPS for the mitotic spindle.

作者信息

Kalab Petr, Heald Rebecca

机构信息

Laboratory of Cell and Molecular Biology, National Cancer Institute, Bethesda, MD 20892-4256, USA.

出版信息

J Cell Sci. 2008 May 15;121(Pt 10):1577-86. doi: 10.1242/jcs.005959.

Abstract

The GTPase Ran has a key role in nuclear import and export, mitotic spindle assembly and nuclear envelope formation. The cycling of Ran between its GTP- and GDP-bound forms is catalyzed by the chromatin-bound guanine nucleotide exchange factor RCC1 and the cytoplasmic Ran GTPase-activating protein RanGAP. The result is an intracellular concentration gradient of RanGTP that equips eukaryotic cells with a ;genome-positioning system' (GPS). The binding of RanGTP to nuclear transport receptors (NTRs) of the importin beta superfamily mediates the effects of the gradient and generates further downstream gradients, which have been elucidated by fluorescence resonance energy transfer (FRET) imaging and computational modeling. The Ran-dependent GPS spatially directs many functions required for genome segregation by the mitotic spindle during mitosis. Through exportin 1, RanGTP recruits essential centrosome and kinetochore components, whereas the RanGTP-induced release of spindle assembly factors (SAFs) from importins activates SAFs to nucleate, bind and organize nascent spindle microtubules. Although a considerable fraction of cytoplasmic SAFs is active and RanGTP induces only partial further activation near chromatin, bipolar spindle assembly is robustly induced by cooperativity and positive-feedback mechanisms within the network of Ran-activated SAFs. The RanGTP gradient is conserved, although its roles vary among different cell types and species, and much remains to be learned regarding its functions.

摘要

GTP酶Ran在核输入与输出、有丝分裂纺锤体组装以及核膜形成过程中发挥着关键作用。Ran在其结合GTP和GDP的形式之间循环,这一过程由与染色质结合的鸟嘌呤核苷酸交换因子RCC1以及细胞质中的Ran GTP酶激活蛋白RanGAP催化。结果产生了RanGTP的细胞内浓度梯度,为真核细胞配备了一个“基因组定位系统”(GPS)。RanGTP与输入蛋白β超家族的核转运受体(NTRs)结合,介导了该梯度的作用,并产生了进一步的下游梯度,荧光共振能量转移(FRET)成像和计算建模已对这些梯度进行了阐释。在有丝分裂期间,依赖Ran的GPS在空间上指导有丝分裂纺锤体进行基因组分离所需的许多功能。通过输出蛋白1,RanGTP募集了重要的中心体和动粒成分,而RanGTP诱导纺锤体组装因子(SAFs)从输入蛋白中释放,从而激活SAFs以形成、结合并组织新生的纺锤体微管。尽管相当一部分细胞质SAFs是活跃的,且RanGTP仅在染色质附近诱导部分进一步激活,但Ran激活的SAFs网络内的协同作用和正反馈机制有力地诱导了双极纺锤体组装。RanGTP梯度是保守的,尽管其作用在不同细胞类型和物种之间有所不同,但其功能仍有许多有待了解之处。

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