Fig. 1.

Network of interactions and reactions in the Ran pathway and the downstream cascade of gradients. (A) Coupling of the RanGTP signal to the dynamics of NTR-cargo interactions in the mitotic cell. The driving force is the steep gradient of free RanGTP, which is produced by RCC1 on the chromatin and dissipated by diffusion-limited reactions that include RanGAP-catalyzed GTP hydrolysis on Ran and the interactions of free RanGTP with NTRs. For simplicity, multi-step reactions are condensed into one step and only one NTR, importin β, is included. Ran is charged with GTP in a RCC1-catalyzed reaction on the surface of the chromatin and diffuses to the cytoplasm where it is either immediately converted to RanGDP in a reaction catalyzed by RanGAP, or interacts with abundant competing cytoplasmic NTRs. Binding ofRanGTP to the importin β-SAF complex produces a RanGTP-importin β complex and liberates an active SAF. RBDs dissociate RanGTP from its complex with importin β and present it for RanGAP-catalyzed GTP hydrolysis. The diagram is based on the Virtual Cell (http://vcell.org) model of the RanGTP gradient (Kalab et al., 2006). (B) The components of the Ran-NTR system form chromatin-centered concentration gradients that exist in parallel in the mitotic cytoplasm and are related to each other in a distinct regulatory order. As the spatial extent of the gradients is defined by the reactions that create and dissipate the individual molecular species and the diffusion rate of those species (Bastiaens et al., 2006; Caudron et al., 2005), the concentration gradient of the more stable RanGTP–importin-β complex is broader than that of active SAFs that have been liberated by RanGTP from importin β-SAF complexes. Note that the extent of the RanGTP–importin-β gradient is expected to be similar to that of the RanGTP–exportin-1–NES cargo complex.