FIGURE 2.

Involvement of Ran in proliferative signaling of cancer cells. Ran is a key player in a positive feedback loop that enhances growth signaling and promotes tumorigenesis. Owing to its ability to affect the import of critical transcription factors (i.e., Erk, p65, Mcl2, β-catenin), RanGTP transmits growth signals from the cytoplasm to the nucleus. RanGTP is also involved in the export of pre-mRNA which are further processed and translated into growth factors [i.e., epidermal growth factor (EGF), SMOC-2) which activate several tyrosine kinase receptors [i.e., EGF receptor (EGFR), platelet-derived growth factor receptor (PDGFR), transforming growth factor beta receptor (TGFβR)] after their release to the extracellular compartment. In addition, Ran is activated following the induction of growth signaling through the phosphorylation of RanBP3 by Akt and ribosomal protein S6 kinase (RSK). Furthermore, besides its ability to modulate the activity of these receptors, Ran is involved in supporting Met signaling through (i) its stabilization by blocking its proteolytic cleavage by metalloproteases and preventing receptor shedding and (ii) the activation of RanBP9 that recruits Son of Sevenless (SoS) which acts upstream of the GTPase Ras.