Regulation of the orphan receptor TR3 nuclear functions by c-Jun N terminal kinase phosphorylation
Regulation of the orphan receptor TR3 nuclear functions by c-Jun N terminal kinase phosphorylation
复制标题
c-Jun N 末端激酶磷酸化调节孤儿受体 TR3 核功能
DOI：
10.1210/en.2006-0800
复制
发表时间：
2007-01-01
期刊：
影响因子：
4.8
通讯作者：
Wu, Qiao
中科院分区：
文献类型：
--
作者：
Liu, Bo;Wu, Jia-Fa;Wu, Qiao
孤儿受体TR 3在细胞核中作为转录因子起作用，以负或正调节基因表达。c-Jun N-末端激酶（JNK）磷酸化在调节TR 3的核功能中起重要作用。虽然TR 3是JNK的磷酸化靶点，但JNK对TR 3功能的调控机制仍有待阐明。我们发现JNK激活剂茴香霉素通过JNK 1而不是p38和ERK信号诱导TR 3磷酸化，这是由其上游因子MAPK激酶4和MAPK激酶7介导的。我们还确定了JNK的确切磷酸化位点是TR 3 N端的丝氨酸95，在其周围存在经典的JNK磷酸化基序。此外，我们证明了TR 3的磷酸化与JNK的泛素化和降解相一致，导致其促有丝分裂活性的丧失。最后，我们发现JNK诱导的磷酸化阻断了TR 3的DNA结合特性，从而降低了其反式激活活性。综上所述，我们的研究结果揭示了TR 3和JNK信号通路之间的一种新的串扰，并阐明了JNK磷酸化依赖性调节TR 3核功能的机制。
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.