Grant: Operating Grant - PA: Institute of Genetics (Bridge Funding)

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 the mechanism of action of Hh proteins comes from studies in the fruit fly, Drosophila melanogaster. These studies have shown that the main initiator of intracellular signaling in response to Hh is a protein called Smoothened (Smo). Upon exposure of cells to Hh, Smo becomes activated, moves to the cell surface, and signals through a series of downstream proteins to regulate gene expression in the nucleus. We have shown that a protein called G protein-coupled receptor kinase 2 (Gprk2) is involved in Hh signaling in flies. Tissues from flies lacking Gprk2 show excessive accumulation of Smo on the surface of cells exposed to Hh, suggesting that Gprk2 is required for internalization of Smo into cells after it has been activated. Loss of Gprk2 also impairs changes in gene expression in response to Hh. Our studies are aimed at identifying the molecular mechanisms by which Gprk2 controls Smo internalization and how this contributes to Hh signaling. 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 signaling can be misregulated in disease.