The RanGTP Pathway: From Nucleo-Cytoplasmic Transport to Spindle Assembly and Beyond

Abstract

The small GTPase Ran regulates the interaction of transport receptors with a number of cellular cargo proteins. The high affinity binding of the GTP-bound form of Ran to import receptors promotes cargo release, whereas its binding to export receptors stabilizes their interaction with the cargo. This basic mechanism linked to the asymmetric distribution of the two nucleotide-bound forms of Ran between the nucleus and the cytoplasm generates a switch like mechanism controlling nucleo-cytoplasmic transport. Since 1999, we have known that after nuclear envelope breakdown (NEBD) Ran and the above transport receptors also provide a local control over the activity of factors driving spindle assembly and regulating other aspects of cell division. The identification and functional characterization of RanGTP mitotic targets is providing novel insights into mechanisms essential for cell division. Here we review our current knowledge on the RanGTP system and its regulation and we focus on the recent advances made through the characterization of its mitotic targets. We then briefly review the novel functions of the pathway that were recently described. Altogether, the RanGTP system has moonlighting functions exerting a spatial control over protein interactions that drive specific functions depending on the cellular context.

Keywords: RanGTP; SAF; cell division; exportin; importin; microtubule; nucleo-cytoplasmic transport; spindle.

Figure 1

The Ran system and its moonlighting functions. (A) Schematic representation of the Ran system for the spatial control of NLS and NES carrying proteins. In cells Ran is found in two forms, RanGTP (green), and RanGDP (light green). RCC1 (light blue) promotes the exchange of GDP to GTP, while RanGAP1-RanBP2 (in pink and purple) promote the hydrolysis of GTP into GDP. RanGTP binds to the importins (turquoise green) and exportins (light purple). Exportins in complex with RanGTP can associate to the NES-proteins (in brown). On the other hand, the binding of RanGTP to importins trigger their dissociation from NLS-proteins (yellow). (B) During interphase, the Ran system controls the nucleo-cytoplasmic shuttling of proteins, because RanGTP is predominant in the nucleoplasm and RanGDP is predominant in the cytoplasm (Sorokin et al., 2007). (C) During mitosis the association of RCC1, the RanGEF, with the chromosomes defines a gradient of RanGTP concentrations that promote the release of SAFs and MT nucleation around the chromatin. The Ran system is converted into a pathway for MT assembly and organization that is essential for mitotic spindle assembly. The RanGTP pathway depends on the establishment of a concentration gradient of RanGTP that peaks around the chromosomes (Kalab et al., ; Caudron et al., 2005). (D) At the end of mitosis, the Ran system also regulates nuclear membrane and NPC reassembly by controlling membrane fusion and releasing NPC components (Walther et al., ; Harel et al., 2003). (E) In ciliated cells RanGTP accumulates in the cilioplasm and promotes the transport and accumulation of Kif17 and retinis pigmentosa 2 to the cilioplasm (Dishinger et al., ; Fan et al., ; Hurd et al., 2011). (F) In neurons many SAFs have a function. Furthermore, importins localize to the dendritic synaptic space and are involved in the transport of cargos to the nucleus (Jordan and Kreutz, ; Panayotis et al., 2015). The Ran system is also active in the axon of the sciatic nerve, where upon injury importins promote the transport of cargos toward the neuron cell body (Hanz et al., ; Yudin et al., 2008).