Hedgehog Signaling in Development and Metabolism

Abstract: Hedgehog (Hh) signaling controls growth and patterning during embryonic development and homeostasis in adult tissues. Dysregulation of Hh signaling is implicted in many human disorders, including several types of cancer. Hh binding to the 12-transmembrane protein Patched (Ptc) elicits intracellular signaling by relieving Ptc-mediated inhibition of the 7-transmembrane protein Smoothened (Smo). Despite significant progress, key questions persist regarding the mechanisms by which Ptc inhibits Smo in the absence of Hh and how Hh stimulation alleviates this inhibition. In the past years, this team has generated new insights into Hh signaling mechanisms, including: 1) Smo phosphorylation by multiple kinases, which leads to Smo cell surface accumulation and signaling activity; 2) Smo sumoylation induced by Hh, which activates Smo; 3) Smo ubiquitination that downregulates Smo cell surface accumulation and promotes Smo endocytosis; and 4) Smo activation by Phosphatidyl-inositol 4-phosphate (PI(4)P) and phosphatidic acid (PA) through direct interaction with Smo C-tail and transmembrane helixes, respectively. The goal of this research program is to understand how Hh signals are sensed and transmitted to control downstream biological events that ultimately govern cell growth and patterning. Proposed studies use a combination of genetic and biochemical approaches to build on prior contributions and to transition to newly emergent avenues of inquiry. The knowledge gained from the proposed studies will provide novel insights into mechanisms surrounding Smo suppression by Ptc and activation by cholesterol, PI(4)P, and PA. In addition, expected outcomes will provide novel insights into human developmental disorders and adult neurodegenerative diseases and will promote development of diagnostic tools and novel therapeutic approaches to transform current concepts of Hh signaling in cancer and neurodegenerative diseases.