G-protein-coupled receptor-mediated signal transduction and its role(s) in development.
G protein-coupled signaling plays a major role in regulating cell movement and cell behavior. These signals effect things from neuronal growth cone extension to immune cell function to embryonic cell movement to cancer metastasis. The Saxe lab focuses on the molecular mechanisms that underlie these signals. The model used is the cAMP signaling system in the eukaryotic microbe Dictyostelium. Extracellular cAMP signaling is known to effect changes in gene expression, morphogenetic cell movements and pattern formation in this organism. All of these effects are mediated through a family of four receptors that show temporal and spatial differences in distribution as well as differences in affinity for ligand. We have taken a genetic approach to defining the signaling pathways regulated by two of these receptors, cAR1 and cAR2. In particular we have isolated mutations that effect signaling between the receptors and the actin cytoskeleton. Among the genes identified is Scar (suppressor of cAR defect) which has revealed a widely conserved family of actin regulating proteins. Scar proteins are found in organisms from Dictyostelium to humans and play a critical role in regulating actin polymerization at the leading edge of motile cells and in endocytosis. Scar is related to WASp, the protein defective in the human immunodeficiency disease, Wiskott-Aldrich Syndrome. We are using a variety of molecular, genetic, biochemical, immunological and microscopic techniques to fully characterize the relationship between receptor signaling and Scar/WASp directed cell movement (e.g. chemotaxis). It is believed that the basic mechanisms that regulate Scar/WASp function in Dictyostelium will have recognisable counterparts in metazoan systems.
