POLYCYSTIN-1 TAIL CLEAVAGE: A NOVEL PKD SIGNALING PATHWAY

ADPKD是最常见的常染色体遗传疾病之一，影响约1/1000人。它的特征是进行性肾囊肿发展，通常在中年晚期导致终末期肾脏疾病。ADPKD是由分别编码多囊蛋白1 （PC1）和多囊蛋白2 （PC2）的PKD1或PKD2基因突变引起的。PC1是一种膜蛋白，可能参与细胞间接触部位的信号传递，而PC2是一种跨膜蛋白，与钙通道具有同源性。这两种蛋白似乎参与相同的信号通路；然而，它们的功能在很大程度上是未知的。一种新的信号模式被称为调节膜内蛋白水解（RIP）最近被描述。在这个模型中，跨膜受体的细胞质部分是

ADPKD is one of the most common autosomal genetic disorders, affecting approximately 1/1000 individuals. It is characterized by progressive renal cyst development, typically leading to end stage renal disease in late middle age. ADPKD is caused by mutations in the PKD1 or PKD2 genes, which encode the polycystin-1 (PC1) and polycystin-2 (PC2) proteins, respectively. PC1 is a membrane protein that may be involved in signaling from sites of cell-cell contact, while PC2 is a transmembrane protein that shares homology with calcium channels. These two proteins appear to participate in the same signaling pathway; however, their functions are largely unknown. A new signaling paradigm known as regulated intramembrane proteolysis (RIP) has been recently described. In this model, the cytoplasmic portion of a transmembrane receptor is released after ligand interaction and enters the nucleus, where it directly acts as a modulator of gene expression. During the previous funding period of this award we have found that PC1 undergoes a RIP-like proteolytic cleavage that releases its C-terminal tail (CTT), which enters the nucleus and initiates signaling processes. The cleavage occurs in vivo in association with alterations in mechanical stimuli. PC2 modulates the signaling properties of the PC1 CTT, and appears to serve as a cytoplasmic buffer that modulates the quantity of CTT available to enter the nucleus. In order to explore further the role that this cleavage plays in the normal functioning of the polycystin proteins and in the pathogenesis of ADPKD we will 1) identify the enzyme responsible for the release of the PC1 CTT; 2) identify the stimuli and signaling pathways that induce or prevent the cleavage and 3) identify the protein partners with which the CTT fragment interacts and define the collection of genes whose expression is altered through nuclear translocation of the CTT fragment. These studies will begin to unravel the relationship between the cleavage of the PC1 CTT and the pathogenesis of ADPKD, and may perhaps suggest new targets for therapeutic intervention.