POLYCYSTIN-1 TAIL CLEAVAGE: A NOVEL PKD SIGNALING PATHWAY

ADPKD是最常见的常染色体遗传性疾病之一，约占1/1000。肾囊肿是一种慢性肾脏疾病，常发生在肾脏，如肾囊肿。ADPKD由PKD 1或PKD 2基因突变引起，PKD 1或PKD 2基因分别编码多囊蛋白-1（PC 1）和多囊蛋白-2（PC 2）蛋白。PC 1是一种膜蛋白，可能参与来自细胞-细胞接触位点的信号传导，而PC 2是一种跨膜蛋白，与钙通道具有同源性。这两种蛋白质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。最近描述了一种新的称为调节性膜内蛋白水解（RIP）的信号传导模式。在该模型中，跨膜受体的细胞质部分是 在配体相互作用后释放并进入细胞核，在那里它直接作为基因表达的调节剂。在该奖项的上一个资助期间，我们发现PC 1经历了RIP样蛋白水解裂解，释放出其C末端尾（CTT），进入细胞核并启动信号传导过程。在体内发生的切割与机械刺激的变化。PC 2调节PC 1 CTT的信号传导特性，并且似乎充当调节可进入细胞核的CTT的量的细胞质缓冲液。为了进一步探索这种切割在多囊蛋白的正常功能和ADPKD的发病机制中所起的作用，我们将1）鉴定负责PC 1 CTT释放的酶; 2）鉴定刺激和信号通路， 诱导或阻止切割和3）鉴定与CTT片段相互作用的蛋白质配偶体，并确定其表达通过CTT片段的核易位而改变的基因的集合。这些研究将开始阐明PC 1 CTT的裂解与ADPKD发病机制之间的关系，并可能为治疗干预提供新的靶点。

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.