MIM regulates Shh target gene expression in tumors

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DESCRIPTION (provided by applicant): The long-term goal of this project is to understand how unregulated epithelial proliferation and invasion leads to carcinogenesis. Sonic hedgehog (Shh) signaling controls the proliferation and migration of progenitor cells of many organs, and uncontrolled Shh target gene induction promotes growth and invasion of 25% of human cancers including lung, breast, prostate, pancreatic, as well as medulloblastoma and basal cell carcinoma. While the Gli family of transcription factors mediates the transcriptional effects of Shh, the mechanism for controlling Gli transcriptional output and Shh-dependent migration and invasion during normal and oncogenic contexts remain poorly understood. Shh signaling components including Suppressor of fused (Sufu) and Smoothened have been shown to concentrate at the primary cilia, a dynamic microtubule-based signaling organelle. Primary cilia are found on most mammalian cells and Shh signaling components concentrate at the cilia in order to regulate Gli3 cleavage and Gli1/2 activation. Loss of cilia leads to defects in Shh signaling and a variety of developmental defects and disorders that range from certain types of retinal degeneration and hair loss to polycystic kidney/liver disease and Bardet-Biedl syndrome. We have identified a novel Shh pathway member, Missing in Metastasis (MIM), a BAR-domain protein that regulates membrane dynamics and whose levels are altered in a variety of epithelial cancers and negatively correlates with outcome in breast cancer. So far, we have established that MIM is required for Shh target gene induction in many cell types and cooperates with the tumor suppressor Sufu, a major negative regulator of Shh signaling, and the Gli oncogene to recapitulate Shh-mediated epithelial proliferation and invasion. In addition, MIM is required for primary cilia formation. Our working hypothesis is that MIM functions to regulate Shh target gene expression in tumors by promoting primary cilia formation and antagonizing Sufu. This proposal seeks to utilize a combination of biochemical, cell biological, and genetic techniques to: 1) Determine the mechanism by which MIM regulates membrane dynamics during ciliogenesis and 2) Determine the mechanism of MIM-dependent potentiation of Sonic hedgehog signaling at the primary cilium. Funding this fellowship will allow us to gain insight into Shh-mediated tumor growth and invasion and Shh signaling in cilia-related disorders.