Mechanistic study of Hedgehog signaling in the cilium

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PROJECT SUMMARY Defects in Hedgehog (Hh) signaling is widely implicated in various birth defects and cancers. The transduction of Hh signaling relies on the primary cilium, a miniature cell surface organelle viewed as a signaling hub. Smoothened (Smo), the core switch of Hh signaling, translocates to the cilium to turn on the Hh signaling. At the molecular level, the signaling mechanisms downstream of Smo are poorly understood. This creates a large barrier to the development of pathway specific treatments for Hh- related disorders. Our overarching goal is to elucidate mechanistic insights into Smo-related signaling events during Hh transduction. To achieve this goal, we have established a proteomic flatform to systematically identify Smo interacting proteins. Our pilot study in this flatform identified the catalytic subunit of PKA as a Smo interacting proteins. We will innovate into the unknown areas of Hh signaling by achieving two objectives: 1) systematically defining the Smo interacting proteins over the course of Hh signal transduction with functional proteomics; 2) deciphering the mechanistic link between Smo and PKA in the cilium during Hh signal transduction and Hh-related tumorigenesis. Our approach is innovative because it employs cutting-edge molecular tools to answer a long-standing question in the Hh pathway. Its significance is underlined by the expectation that it will shed light on long-standing questions about Smo signaling in the Hh pathway, which will ultimately provide clues for the development of new therapeutical methods for Hh-related cancers. This grant will give me opportunity to engage students from underrepresented groups. My goal is to build solid research foundations for these students for their future pursuit of careers in cancer field, helping to diversify the workforce in basic study of cancers research.