STAT3 nuclear import is independent of tyrosine phosphorylation and mediated by importin-alpha3.
Signal transducer and activator of transcription (STAT)3 is a member of a family of DNA-binding factors that function to induce expression of responsive genes. STAT3 can act as an oncogene, and its function has been shown to be critical for cellular transformation by a number of oncogenic tyrosine kinases. The role of STAT3 as a DNA-binding transcription factor naturally depends on its ability to gain entrance to the nucleus. In this study, we provide evidence that STAT3 is distinct from previously characterized STAT molecules in that it dynamically shuttles between cytoplasmic and nuclear compartments and maintains prominent nuclear presence. Although tyrosine phosphorylation is required for STAT3 to bind to specific DNA target sites, nuclear import takes place constitutively and independently of tyrosine phosphorylation. We identify a region within the coiled-coil domain of the STAT3 molecule that is necessary for nuclear import and demonstrate that this region is critical for its recognition by specific import carrier importin-alpha3. RNA interference studies were used to verify the role and specificity of importin-alpha3 in STAT3 nuclear translocation. These results distinguish STAT3 cellular localization from other STAT molecules and identify a feature that may be targeted in the clinical intervention of STAT3-dependent neoplasia.
Liu
Ling
L
Department of Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, NY 11794-8691, USA.
McBride
Kevin M
KM
Reich
Nancy C
NC
D021581:Active Transport, Cell Nucleus; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D028884:Karyopherins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor; D017384:Sequence Deletion / Q000235:genetics; D015534:Trans-Activators / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism*
D004268:DNA-Binding Proteins; D028884:Karyopherins; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D014443:Tyrosine