Structural Mechanisms of Hedgehog Autoprocessing in Physiology and Disease

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The Hedgehog (Hh) signaling pathway plays important roles in development and in cancer. The Hh ligand, which activates the pathway, is derived from the autoprocessing of the Hh precursor protein. Hh autoprocessing is at the very beginning of the Hh signaling pathway and likely plays crucial roles in both physiology and disease. However, the basic mechanisms of Hh autoprocessing and its role in diseases are poorly understood. Using an interdisciplinary approach, we will define the catalytic mechanism of Hh autoprocessing with atomic resolution and study two novel roles for Hh autoprocessing in prostate cancer. We will first define the catalytic mechanism of Hh autoprocessing with solution NMR; we will then study a new mechanism of tumorigenesis involving zinc deficiency and Hh activation in prostate cancer; lastly we will establish Hh autoprocessing of cancer drugs as a novel means of drug resistance in prostate cancer.