Structural Mechanisms of Hedgehog Autoprocessing in Physiology and Disease

Hedgehog(HH)信号通路在发育和癌症中发挥重要作用。HH配体， 它激活了该途径，来自于HH前体蛋白的自动处理。HH 自动处理是HH信号通路的最开始，可能在这两个过程中都扮演着关键的角色 生理学和疾病。然而，HH自身处理的基本机制及其在疾病中的作用是 人们对此知之甚少。使用跨学科的方法，我们将定义HH的催化机理 具有原子分辨率的自动处理，并研究前列腺癌HH自动处理的两个新角色。我们 我们将首先用溶液核磁共振确定HH自动处理的催化机理；然后我们将研究一种新的 前列腺癌中锌缺乏和HH激活的致瘤机制；最后我们将 建立抗癌药物的HH自动加工作为前列腺癌耐药的新手段。

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.