Hypothesis: Ligand/Receptor-Assisted Nuclear Translocation of STATs

Abstract

The STAT transcription factors are mediators of signal transduction of a variety of factors, including interferons (IFNs), interleukins, growth factors, and peptide hormones. Subsequent to activation, STATs are translocated to the nucleus apparently through the well-described importin/Ran system, where they activate target genes. Molecules utilizing this nuclear import system require specific nuclear localization sequences (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 receptors that signal through STATs contain putative NLSs and, where examined, either ligand or receptor undergoes nuclear translocation. We hypothesize that ligands and/or their receptors serve as vehicles for the nuclear 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 functional NLS has been identified in a C-terminal domain of IFNgamma. This domain and the NLS contained within are crucial for the biological properties of IFNgamma in that a peptide encompassing this domain is sufficient to induce an antiviral state. Further, this domain binds specifically to a membrane-proximal region internal cytoplasmic domain of the alpha 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 are associated with the ligand-receptor complex.

Differential Effects of Prolactin andsrc/abl Kinases on the Nuclear Translocation of STAT5B and STAT5A

“…However, no conventional nuclear localization signals have been identified in the STAT proteins. In fact, it has been hypothesized that a ligand-receptor complex might function as a chaperone to facilitate STAT nuclear import (45,46). Such a mechanism appears unlikely to account for the selective nuclear import of STAT5B by the src/abl kinases.…”

STAT proteins: novel molecular targets for cancer drug discovery

“…STAT tyrosine phosphorylation is therefore not su cient for translocation. On the question of STATs possessing authentic nuclear localization sequences (NLS), this is not widely believed to be the case (Johnson et al, 1998b), raising the possibility of a distinct nuclear translocation mechanism whose induction signal originates from STAT proteins. There is some evidence that the phosphorylation of a critical tyrosine residue of the activating receptor is essential in recruiting intracellular components that regulate interactions of STAT dimers with cellular proteins in the cytoplasm, events that may modulate STAT nuclear translocation (Ali and Ali, 1998).…”

Differential Properties of Two Putative Nuclear Localization Sequences Found in the Carboxyl-Terminus of Human IFN-γ

“…(5) These studies are in agreement with a concept that the necessary basic NLS required for Stat1a interaction with NPI-1 is provided by another molecule in association with Stat1a. (7,8) It has been shown in our laboratory that the carboxyl-terminus of murine IFN-g (MuIFN-g) contains a functional polybasic NLS. (9) This NLS directly regulates the intracellular association of Stat1a to the importin, NPI-1.…”