RAN is a member of the Ras family of small GTPases, and is distinguished from other Ras GTPases by its lipid modification and atypical subcellular localization. RAN protein occurs throughout the cell but is concentrated in the nucleus. RAN is regulated by a cytosolic protein, RANGAP1 and by a nuclear protein, RANGEF. The distribution of RAN-GTP provides important spatial information that directs cellular activities during different parts of the cell cycle. During interphase, the localization of RANGEF and RANGAP1 predicts that nuclear RAN is GTP-bound and cytosolic RAN is GDP-bound. This compartmentalization determines the direction of nuclear transport by promoting the loading and unloading of transport receptors in a manner that is appropriate to the nucleus or cytosol.RAN plays a critical role in nucleo-cytoplasmic transport of macromolecules through the nuclear pore complex (NPC) by promoting assembly and disassembly reactions of transport receptors and cargo. Proteins destined for the nucleus contain a nuclear localization signal (NLS), whereas proteins destined for the cytoplasm contain a nuclear export signal (NES). The import of proteins having NLS, to the nucleus through NPCs, is mediated primarily by the importin-α/β complex. In the cytoplasm, NLS bearing cargo proteins binds to importin-β via the importin-α adaptor. Binding to the importin complex facilitates passage through NPCs to the nucleus, where the import complex is dissociated by RAN-GTP, a Ras-family GTPase. The importins are then recycled to the cytoplasm with importin-β complexed with RAN-GTP and importin-α complexed with both RAN-GTP and its nuclear export factor, CAS, which is a member of the importin-β superfamily of karyopherins. Finally, cytoplasmic RANGAP and its co-activators, RANBP1 and RANBP2, activate RAN-GTP hydrolysis, releasing the importins for a further protein import cycle. GTP hydrolysis by RAN provides the energy for the nuclear protein import cycle. In contrast, export receptors bind NES cargo in the nucleus together with RANGTP. Translocation of the receptor-NES cargo-RANGTP export complex to the cytoplasm is followed by GTP hydrolysis, which triggers disassembly of the complex and release of NES cargo and exportin.
The generation of RAN-GTP occurs only in the nucleus by RANGEF that catalyzes GDP release and GTP binding. RAN is charged with GTP in the nucleus by its GEF; RCC1, whereas RANGAP stimulates GTP hydrolysis in the cytoplasm, after which RAN-GDP is recycled to the nucleus by NTF2. Thus, the appropriate nucleocytoplasmic distribution of RAN is maintained by a balance between nuclear export of RAN-GTP in association with transport receptors, and nuclear import of RAN-GDP mediated by NTF2. The high concentration of RAN-GTP in the nucleus favors assembly of export complexes and disassembly of import complexes. In addition to movement of proteins between the nucleus and cytoplasm, RAN also takes part in RNA transport. (Upgraded 09/2019)