Regulation of fission yeast cell polarity by stress-signalling pathways (360G-Wellcome-210659_Z_18_Z)

Cell polarity is essential to eukaryotic cell organisation and function and important in cell/tissue homeostasis and disease. Cdc42 and other Rho-family GTPases have widely-conserved, central roles in cell polarity. Using fission yeast Schizosaccharomyces pombe, we discovered that Cdc42-mediated cell polarity is regulated by the stress-activated protein kinase (SAPK) pathway, involving MAP kinase Sty1, homologous to mammalian p38. Although the SAPK pathway is known to regulate gene expression in response to stress, our work suggests that stress signalling regulates cell polarity post-translationally, via novel pathways. Our overall goal is to understand, at a molecular level, how SAPK activation leads to Cdc42-module regulation, through combined proteomics, genetics, imaging, and biochemistry approaches. We will identify polarity-specific substrates of Sty1 and determine how they influence Cdc42 and its interactors. We will also study the two different Cdc42 guanine-nucleotide exchange factors, as we have shown that they have distinct roles in polarity regulation and are oppositely affected by stress. We will also determine how SAPK-regulation of cell-polarity is integrated with other signalling pathways, including nutrient stress/TOR signalling, cell-cycle control, and the cytoskeleton. This work in a model eukaryote will provide insights into potential roles of stress signalling in cell polarity in humans and pathogenic fungi.