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First published online May 8, 2008
doi: 10.1242/10.1242/jcs.005959

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The RanGTP gradient – a GPS for the mitotic spindle

¹ Laboratory of Cell and Molecular Biology, National Cancer Institute, Bethesda, MD 20892-4256, USA
² Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, CA 94720-3200, USA

^* Author for correspondence (e-mail: pkalab{at}yahoo.com)

Accepted 27 March 2008

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 β 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.

Key words: Ran, Importin, Exportin, Mitotic spindle, Cancer