Regulation of the orphan receptor TR3 nuclear functions by c-Jun N terminal kinase phosphorylation.
The orphan receptor TR3 functions in the nucleus as a transcription factor to negatively or positively regulate gene expression. c-Jun N-terminal kinase (JNK) phosphorylation plays an important role in modulating the nuclear functions of TR3. Although TR3 is the phosphorylation target of JNK, the regulatory mechanism of JNK on TR3 functions remains to be elucidated. Here we showed that JNK activator anisomycin induced TR3 phosphorylation through JNK1 rather than p38 and ERK signals, which is mediated by its upstream factors MAPK kinase 4 and MAPK kinase 7. We also identified the exact phosphorylation site of JNK to be serine 95 at the N terminus of TR3, around which a classical JNK phosphorylation motif exists. Furthermore, we demonstrated that TR3 phosphorylation by JNK coincided with its ubiquitination and degradation, resulting in the loss of its mitogenic activity. Finally, we showed that JNK-induced phosphorylation blocked the DNA binding property of TR3 and hence diminished its transactivation activity. Taken together, our findings revealed a novel cross talk between TR3 and JNK signal pathway and shed light on the mechanism of JNK phosphorylation-dependent regulation on TR3 nuclear functions.
Liu
Bo
B
Department of Biomedical Sciences, School of Life Sciences, Xiamen University, Xiamen 361005, Fujian, China.
Wu
Jia-fa
JF
Zhan
Yan-yan
YY
Chen
Hang-zi
HZ
Zhang
Xiao-yan
XY
Wu
Qiao
Q
D002455:Cell Division / Q000502:physiology; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D007668:Kidney / Q000166:cytology; D008156:Luciferases / Q000235:genetics; D008934:Mitogens / Q000235:genetics / Q000378:metabolism; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D010766:Phosphorylation; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism
D004268:DNA-Binding Proteins; D008934:Mitogens; C539821:NR4A1 protein, human; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011987:Receptors, Steroid; D011988:Receptors, Thyroid Hormone; D012694:Serine; D008156:Luciferases; D048031:JNK Mitogen-Activated Protein Kinases