Regulatory Mechanism of Stress-Responsive Signal Transduction Pathway

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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.