Molecular regulation of STAT3 activation and nuclear translocation stimulated by growth factors & Cytokines

Abstract

Abstract: STATs are a family of latent cytoplasmic transcription factors. Upon stimulation, tyrosine-phosphorylated STAT proteins undergo dimerization and subsequently translocate into the nucleus. Although much has been learned about the structure and function of STATs, less is known about how STAT proteins translocate into the nucleus. We found in this study that ligand-induced Stat3 nuclear import is mediated by importin I?5 and importin I?7. Two sequence elements, Arg214/215 and 414/417 are required for the nuclear import of Stat3, while Arg214/215 is likely to be involved in direct interaction with importin I?5, Arg414/417 may regulate Stat3 nuclear transport via an indirect manner, such as maintaining the proper conformation of Stat3 dimer. We also found that the adaptor protein Grb2 regulates Stat3 activation negatively at the receptor level by competitive binding to the EGFR, thus ablate the tyrosine phosphorylation of Stat3.