Grant: Operating Grant

Hedgehog (Hh) proteins are an evolutionarily-conserved family of growth factors that are secreted from cells and convey information to neighbouring cells within tissues. These proteins play a critical role in controlling the growth and organization of embryonic and fetal tissues in species ranging from flies to man. They are also important for stem cell function, and consequently for maintenance of adult tissues. Due to their central role in these processes, misregulation of Hh activity can result in congenital birth defects and cancer. Much of our understanding of how Hh proteins work comes from studies in the fruit fly, Drosophila melanogaster. The main initiator of intracellular signaling in response to Hh is a protein called Smoothened (Smo). Upon exposure of cells to Hh, Smo moves to the cell surface and becomes active, sending a signal that is relayed to the nucleus to change patterns of gene expression. We have shown that a protein called G protein-coupled receptor kinase 2 (Gprk2) is involved in Hh signaling in flies, as loss of this protein affects Smo regulation and blocks changes in gene expression in response to Hh. Our studies are aimed at identifying how Gprk2 regulates Smo, and how this contributes to the relay of the Hh signal to the nucleus. Gprk2-related proteins in mammals have also been implicated in Hh signaling. Thus, we expect that our studies in flies will provide important basic insights into how Hh proteins normally signal in humans, and how this can be misregulated in disease.