Nuclear retention of STAT3 through the coiled-coil domain regulates its activity.
Signal transducer and activator of transcription 3 (STAT3), which mediates biological actions in many physiological processes, is activated by cytokines and growth factors via specific tyrosine phosphorylation, dimerization, and nuclear translocation. However, the mechanism involved in its nuclear translocation remains unclear. A previous study demonstrated that STAT3 with Arg-214/215 mutations in the coiled-coil domain (R214A/R215A; STAT3 RA) failed to undergo nuclear translocation. Here, we re-examined the nature of the STAT3 RA mutant and found that it showed higher and more extensive tyrosine-phosphorylation as well as much higher STAT3 transcriptional activity in response to stimuli. Furthermore, STAT3 RA showed nuclear translocation and faster nuclear export than wild-type STAT3 after stimulation. Moreover, nuclear retention of STAT3 RA by a chromosomal region maintenance 1 (CRM1) inhibitor, leptomycin B, decreased the enhanced STAT3 activation by stimuli. These data demonstrate that Arg-214/215 are involved in CRM1-mediated STAT3 nuclear export and the regulation of STAT3 activity.
Sato
Noriko
N
Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-Ku Kita 12 Nishi 6, Sapporo 060-0812, Japan.
Tsuruma
Rieko
R
Imoto
Seiyu
S
Sekine
Yuichi
Y
Muromoto
Ryuta
R
Sugiyama
Kenji
K
Matsuda
Tadashi
T
D021581:Active Transport, Cell Nucleus; D019943:Amino Acid Substitution; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000648:ultrastructure; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D028884:Karyopherins / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D050796:STAT3 Transcription Factor; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000737:chemistry* / Q000378:metabolism*; D000097606:Exportin 1 Protein
D004268:DNA-Binding Proteins; D028884:Karyopherins; D018160:Receptors, Cytoplasmic and Nuclear; D050796:STAT3 Transcription Factor; D015534:Trans-Activators; D000097606:Exportin 1 Protein; C494086:STAT3 protein, human