Hm. Johnson et al., HYPOTHESIS - LIGAND RECEPTOR-ASSISTED NUCLEAR TRANSLOCATION OF STATS/, Proceedings of the Society for Experimental Biology and Medicine, 218(3), 1998, pp. 149-155
The STAT transcription factors are mediators of signal transduction of
a variety of factors, including interferons (IFNs), interleukins, gro
wth factors, and peptide hormones. Subsequent to activation, STATs are
translocated to the nucleus apparently through the well-described imp
ortin/Ran system, where they activate target genes, Molecules utilizin
g this nuclear import system require specific nuclear localization seq
uences (NLSs), Paradoxically, such NLSs are not identifiable on STATs,
thus raising the question of how they are imported into the nucleus,
Of considerable interest is the observation that ligands and/or recept
ors that signal through STATs contain putative NLSs and, where examine
d, either ligand or receptor undergoes nuclear translocation. We hypot
hesize that ligands and/or their receptors serve as vehicles for the n
uclear translocation of STATs, and that they may be directly involved
in signal transduction, Using IFNgamma as a model system, we provide a
possible mechanism for how this direct role is fulfilled. A functiona
l NLS has been identified in a C-terminal domain of IFNgamma, This dom
ain and the NLS contained within are crucial for the biological proper
ties of IFNgamma in that a peptide encompassing this domain is suffici
ent to induce an antiviral state, Further, this domain binds specifica
lly to a membrane-proximal region internal cytoplasmic domain of the a
subunit of the receptor complex in a region that is directly involved
in the recruitment and activation of the JAK/STAT pathway. We suggest
that this novel mode of receptor recognition and activation may be a
driving force for nuclear translocation of molecules like STATs that a
re associated with the ligand-receptor complex.