Molecular mechanisms of STAT3 activation and their therapeutic applications

STAT3蛋白主要由IL-6家族细胞因子、表皮生长因子和瘦素激活。像STAT家族的其他成员一样，STAT3被Jak激酶酪氨酸磷酸化，然后形成二聚体并移位到细胞核中激活靶基因。已有研究表明，单独激活的STAT3可以介导细胞转化。IL-6是1986年我们克隆的B细胞刺激因子2，并发现了它的多种功能及其与多种自身免疫性疾病和癌症的关系。在这些杰出的工作之后，我们继续了对IL-6信号转导机制的研究。尤其是在IL-6/STAT3介导的信号通路中，我们重点研究了STAT3分子，报道了几个正向或负向调节STAT3的分子。我们还利用酵母双杂交系统鉴定了新的STAT3结合蛋白。其中一种是ZIPK，它是一种直接磷酸化STAT3的丝氨酸/苏氨酸蛋白激酶。我们还报道了其他STAT3调节因子，STAP-2，Daxx和LMW-DSP2(Dusp22)。在我们的研究中，我们预计与STAT3直接相互作用的STAT3调节器可能在调节STAT3激活方面发挥关键作用。因此，更详细地了解这些分子和STAT3之间的相互作用是重要的，因为新的信息可能为包括癌症和自身免疫性疾病在内的病理条件提供新的治疗方法。

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.