Regulatory Mechanism of Stress-Responsive Signal Transduction Pathway

应激反应信号转导通路是重要的细胞防御机制。其核心是所谓的应激激活MAP激酶级联（SAPK级联）。哺乳动物SAPK通路的缺陷不仅会导致分子和细胞水平的异常，还会导致自身免疫和癌症等全身性疾病。为了帮助开发这些疑难疾病的新治疗方法，该项目重点关注与SAPK途径有关的各种重要课题，使用人类、小鼠、线虫、酵母和蓝藻。通过本项目，阐明了几种MAP3K酶的新激活机制，即哺乳动物MTK1和ASK1/2以及酵母Ssk2和Ste11。此外，我们还获得了许多关于蛋白磷酸酶、接头蛋白和结合蛋白以及对接相互作用对SAPK通路的正调控和负调控的新发现。利用线虫的研究揭示了SAPK通路在系统水平上的新作用，如先天免疫、氧化应激耐受性和重金属耐受性。酵母HOG渗透调节通路SAPK的调控机制已经被阐明，现在被认为是最容易理解的信号通路之一。哺乳动物的MAPK和SAPK通路与自身免疫、癌症和感染等多种疾病的发病密切相关。因此，这些项目的结果有望通过确定药物开发的潜在靶标分子来帮助开发针对这些疑难疾病的新疗法。由于酵母SAPK通路是致病酵母（如芽孢菌和念珠菌）毒力的重要决定因素，本项目的发现也将有助于开发新的抗真菌药物。综上所述，本项目不仅促进了哺乳动物、线虫、酵母和蓝藻中SAPK信号传导的直接研究领域的发展，而且对其他相关领域也有重要影响。

Stress-responsive signal transduction pathway is an important cellular defence mechanism. Its central core is the so-called Stress-Activated MAP Kinase cascade (SAPK cascade). Defects in mammalian SAPK pathways cause, not only abnormalities at the molecular and cellular levels, but also systemic diseases such as autoimmunity and cancer. In order to aide developments of new treatments for these difficult diseases, this project focused on various important subjects concerning SAPK pathways, using human, mouse, nematode, yeast, and cyanobacterium.Through this project, the novel activation mechanisms of several MAP3K enzymes, namely mammalian MTK1 and ASK1/2 and yeast Ssk2 and Ste11, were elucidated. Furthermore, we obtained numerous new findings concerning positive and negative regulations of SAPK pathways by protein phosphatases, adaptor and binding proteins, and docking interactions. Studies using nematode has revealed new roles of SAPK pathways at systemic level, such as innate immunity, tolerance to oxidative stress, and tolerance to heavy metals. The regulatory mechanism of the yeast HOG osmoregulatory SAPK pathway has been elucidated to the point that it is now considered as one of the best understood signaling pathways.Mammalian MAPK and SAPK pathways are intimately related to pathogenesis of various diseases such as autoimmunity, cancer, and infection. Thus, results from this projects are expected to aide developments of new treatments for these difficult diseases, by identifying prospective target molecules for drug development. Because the yeast SAPK pathway is an important determinant for virulence of pathogenic yeasts such as Blastomyces and Candida, the findings from this project will be also useful to develop new anti-fungal drugs.In conclusion, this project not only contributed to advancement of the immediate field of SAPK signaling in mammalian, nematode, yeast and cyanobacterium, but it also had a significant influence on other related fields.