Spatial and temporal coordination of mitosis by Ran GTPase

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Abstract
Ran, a small Ras-related GTPase, controls the directionality of transport of macromolecules across the nuclear envelope through the nuclear pore complex. RanGTP is generated in the nucleus by a Ran-specific guanine nucleotide-exchange factor, RCC1, whereas GTP hydrolysis by Ran requires its interaction with the GTPase-activating protein RanGAP and Ran-binding proteins. The compartmentalization of these regulators of the GTP–GDP cycle of Ran, together with the active import of Ran into the nucleus, ensures a high concentration of RanGTP in the nucleus. RanGTP functions by binding karyopherins, proteins of the importin and exportin family of transport factors, causing them to either bind (exportins) or release (importins) their transport cargoes. Ran also has important roles during mitosis, when the boundary between the nucleoplasm and the cytoplasm breaks down in animal cells. Production of RanGTP by RCC1 on chromatin during mitosis is proposed to generate a gradient of RanGTP away from chromosomes that provides a spatial signal for the proper assembly of the spindle. Ran directs mitotic spindle assembly by promoting the release of spindle assembly factors from inhibited complexes with importins. RanGTP might also cause the assembly of multimeric protein complexes at specific sites such as kinetochores and centrosomes. Ran, acting through importins, has an important role in the reassembly of the nuclear envelope at the end of mitosis and in the formation of nuclear pore complexes. The Ran system provides examples of the spatial regulation of subcellular organization through diffusible signalling gradients and the control of the assembly multimeric protein complexes on specific structures.