Molecular mechanisms of STAT3 activation and their therapeutic applications

STAT 3蛋白主要由IL-6家族的细胞因子、表皮生长因子和瘦素激活。与STAT家族其他成员一样，STAT 3被Jak激酶酪氨酸磷酸化，然后形成二聚体并易位到细胞核中以激活靶基因。已经表明，活化的STAT 3单独可以介导细胞转化。1986年，我们克隆了IL-6作为B细胞刺激因子2，发现其具有多种功能，并与多种自身免疫性疾病和癌症有关。在完成了这些工作之后，我们继续进行了IL-6信号转导机制的研究。特别地，我们关注IL-6/STAT 3介导的信号通路中的STAT 3分子，并报道了几种正或负调节STAT 3的分子。我们还利用酵母双杂交系统鉴定了新的STAT 3结合蛋白。其中，一种是ZIPK，一种直接磷酸化STAT 3的Ser/Thr激酶。我们还报道了其他STAT 3调节剂，STAP-2，Daxx和LMW-DSP 2（DUSP 22）。在我们的研究中，我们预计与STAT 3直接相互作用的STAT 3调节因子可能在STAT 3激活的调节中起关键作用。因此，更详细地了解这些分子与STAT 3之间的相互作用是重要的，因为新的信息可能为病理条件提供新的治疗方法，包括癌症和自身免疫性疾病。

STAT3 protein is mainly activated by IL-6 family of cytokines, epidermal growth factor, and leptin. Like other members of STAT family, STAT3 is tyrosine-phosphorylated by Jak kinases, then forms a dimer and translocates into the nucleus to activate target genes. It has been shown that the activated STAT3 alone can mediate cellular transformation. We cloned IL-6 as B cell stimularory factor 2 in 1986, and found its multiple functions and the relationship with several autoimmune diseases and cancers. After these outstanding works, we have continued the research concerning the mechanisms of IL-6 signal transduction. Especially, we have focused on STAT3 molecule in the IL-6/STAT3-mediated signaling pathway and reported several molecules, which regulate STAT3 positively or negatively. We also identified novel STAT3 binding proteins by using yeast two-hybrid system. Among them, one is ZIPK, a Ser/Thr kinase which phosphorylates STAT3 directly. We have also reported other STAT3 regulators, STAP-2, Daxx and LMW-DSP2 (DUSP22). In our research, we expect that STAT3 regulators, which directly interact with STAT3, may have critical roles in the regulation of STAT3 activation. More detailed understanding of interactions between these molecules and STAT3 is therefore important as new information may provide novel therapeutic approaches for the pathological conditions, including cancer and autoimmune diseases.