Ste50 plays an important role in the mitogen-activated protein kinase (MAPK) signaling pathway required for filamentous growth of the budding yeast, Saccharomyces cerevisiae, a unicellular eukaryote. More specifically, Ste50 plays a poorly understood role in mediating signal transmission from Ras2 to the MAPK module, which ultimately activates gene expression in the nucleus. This protein contains two recently described sequence elements, a SAM domain and an RA domain, which have been identified by computer pattern searching methods. SAM motifs are found in certain receptor-tyrosine kinases and also in other signaling proteins involved in developmental processes. RA domains are found in novel ras effectors, suggesting that they play a role in signaling by ras or by other small ras-like GTPases. Two parallel approaches will be used to study Ste50: 1) Functionally important associations between the SAM and RA domains and their target proteins will be identified by a combination of molecular genetics, biochemical and mutagenesis approaches; and 2) the structural basis of these interactions will be studied by nuclear magnetic resonance (NMR) spectroscopy. Knowledge of the structural and functional details of the interactions of the SAM and RA domains of Ste50 with their targets might reveal an important mechanism for signal transmission from Ras to MAPK signaling pathways. As aberrant activation of MAPK signaling pathways is implicated in the disease processes leading to several types of cancer and immune disorders, this might help in the development of therapeutic agents for treatment of these diseases. In addition, this knowledge will be useful for understanding the mechanism of association of these two domains with their targets in general.
