Regulatory Mechanism of Stress-Responsive Signal Transduction Pathway in Human and Yeast Cells

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1) Regulatory mechanism of human stress-responsive signal transduction pathwayWe revealed the mechanism of MTK1 activation by the stress-inducible Gadd45 proteins. Gadd45 binds to the N-terminal region of the MTK1, induces an N-C dissociation in MTK1 molecule, and thus facilitates MTK1 dimerization that leads to MTK1 activation by auto-phosphorylation. We showed that TGF-beta activates MTK1 through induction of the expression of Gadd45. We also identified a novel docking interaction between stress-activated MAPKKK (SAP3K) and stress-activated MAPKK (SAP2K). We showed that a C-terminal region in SAP2K, termed the DVD domain, was essential for this interaction, and elucidated its role in SAP2K activation. Using the specific interaction through DVD domain, we developed a new FRET probe to visualize SAP3K activity in single living cells.2) Regulatory mechanism of yeast stress-responsive signal transduction pathway.We identified the mucin-like membrane glycoproteins Hkr1 and Msb2 as putative osmosensors in the Sho1 branch of Hog1 MAPK pathway. We found a specific docking interaction between yeast osmoregulatory Ssk2 SAP3K and Pbs2 SAP2K, and showed that the interaction is essential for specific activation of Pbs2 by Ssk2. We also analyzed the functional roles of the docking interaction between Hog 1 and its activator, the Pbs2 SAP2K, as well as that between Hog1 and its inactivator, the Ptp2 protein tyrosine phosphatase. Finally, we found that the membrane protein Sho1, the cytoplasmic protein Ste50, and the small G-protein Cdc42 serve as adaptor proteins in yeast osmoregulatory Hog1 MAPK pathway.