Hedgehog signaling at the cell's antenna: Smoothened and the primary cilium

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DESCRIPTION (provided by applicant): The Hedgehog pathway is one of the fundamental means of controlling mammalian cell behavior and is used to regulate a wide variety of disparate biological events including tissue patterning, stem cell renewal, and cell proliferation. All Hedgehog signaling in organisms ranging from Drosophila to mice relies on the proto-oncogene Smoothened, mutations in which can cause basal cell carcinoma, the most common cancer in North America, and medulloblastoma, the most common solid cancer among children. Despite its importance to both development and disease, the molecular mechanism by which Smoothened functions remains unclear. We have recently discovered that mammalian Hedgehog signals move Smoothened to an organelle called the primary cilium, and that this movement is necessary for Smoothened activity. Although it is known that almost all mammalian cells possess a single primary cilium that extends into the extracellular environment, the functions of this organelle are poorly understood. We propose that the primary cilium acts as a cellular antenna, through which Hedgehog signals are transduced. We seek to build on these findings to investigate how Smoothened acts at the cilium and whether cilia participate in Smoothened-mediated cancer development. Specifically, we will answer four questions: 1) How is the transport of Smoothened to the primary cilium regulated? 2) How does Smoothened activate its pathway at the cilium? 3) Is Smoothened localization misregulated in cancer? 4) Are primary cilia required for Smoothened-mediated oncogenesis? The proposed experiments use genetic, molecular, and biochemical approaches to answer these questions in normal cells, human tumors, and mouse cancer models. This work will both elucidate the mechanism of Smoothened regulation, and assess the function of primary cilia in development and neoplasia. Taken together, these studies will provide a biochemical and cell biological understanding of how Smoothened and the primary cilium regulate Hedgehog signal transduction both in development and in disease.