Movement of ions, metabolites and other small molecules between nucleus and cytoplasm takes place by passive diffusion; however, transport cargos larger than 40 KDa require the participation of specific receptors and carriers [168, 169] . FG nucleoporins are placed on both cytoplasmic and nucleoplasmic sides of the NPC and play a central role in the active transport of macromolecules. The FG domains of nucleoporins are unfolded regions that participate in energy-independent transient interactions with the cargo receptors during the docking and translocation processes [170] . Nevertheless, the delivery of the cargo and some of the directional steps require hydrolysis of GTP. Trafficking of proteins through NPC is mediated by a family of conserved transport receptors named karyopherins, which recognize short peptides known as nuclear localization signal (NLS) and nuclear export signal (NES) [169, 171] . In addition, Karyopherins also recognize nucleotide sequences during the export of some classes of RNAs [163] . Due to their key role, Karyopherins involved in cargo import are known as importins and those involved in export are known as exportins. The RanGTP cycle also plays a central role in karyopherin activity and, therefore, in trafficking of macromolecules through the NPC. Importins bind the cargo in the cytoplasm and release it on binding to RanGTP in the nucleus. In contrast, exportins bind the cargo in the nucleus together with RanGTP; and then the Ran-associated GTP is hydrolyzed in the cytoplasm by RanGAP and cargo is liberated [163, 164] . Proteins containing constitutively active NLS are predominantly nuclear; but in some cases, the accessibility of NLS or the NLS itself is modified to selectively regulate the localization of the protein [172] . A similar regulatory mechanism is also exerted for control of NES activity [173] . For example, the NLS of the transcription factor NFκB is masked by the interaction with the inhibitor IκBα. However, IκBα is degraded on proinflammatory stimuli, exposing the NLS of NFκB for importin recognition. Therefore, under proinflammatory conditions, NFκB is imported to the nucleus, where it triggers a specific gene response [172] . In addition to "masking strategies," phosphorylation, ubiquitination or methylation of NLS or NES also influences (negatively or positively) their recognition by importins or exportins. Therefore, trafficking of proteins between nucleus and cytoplasm could be finely regulated by posttranslational modifications in the NLS and NES [164, 174] .