Cadherin-PS1-gamma-secretase signal transduction pathway

早老素1（Presenilin 1，PS1）是一种在家族性阿尔茨海默病（familial Alzheimer's disease，FAD）发病中起重要作用的多位整合膜蛋白。 经典钙粘蛋白是I型跨膜糖蛋白，其控制细胞粘附、识别和接触介导的细胞生长抑制中的关键事件。 最近，我们报道，PS1集中在细胞和突触接触网站，它纳入钙粘蛋白/连环蛋白细胞粘附系统。 在这里，我们提出的初步数据，PS1直接结合到E-钙粘蛋白和调节Ca++依赖的细胞-细胞粘附。 此外，我们的研究结果表明，PS1和γ-分泌酶活性控制约20 kDa的钙粘蛋白胞质肽（称为pC 20）的产生，并调节细胞周期蛋白D1和细胞周期蛋白依赖性激酶抑制剂p27 Kip 1，两个重要的细胞周期蛋白的表达。 pC 20似乎来源于称为pC 35的较大的钙粘蛋白前体。 在全长钙粘蛋白的胞质外切割后产生pC 35。在PS1缺陷细胞中钙粘蛋白胞质肽的表达模拟了pC 20的作用，并降低了细胞周期蛋白D1和p27 Kip 1的表达水平。 两者合计，我们的初步数据表明，PS1，钙粘蛋白和γ-分泌酶参与了一种新的信号转导机制，调节细胞周期蛋白的表达。 这种机制可能使用细胞质钙粘蛋白衍生肽pC 20作为转运到细胞核的信使，在那里它控制细胞周期蛋白的表达。 因此，PS1和γ-分泌酶活性可能通过调节钙粘蛋白衍生信息的表达来控制钙粘蛋白信号转导途径。 本申请提出了钙粘蛋白-PS1-γ-分泌酶信号转导通路的特点，并检查其参与阿尔茨海默病。

Presenilin1 (PS1), is a polytopic integral membrane protein that plays important roles in the development of familial Alzheimer's disease (FAD). Classic cadherins are type I transmembrane glycoproteins that control critical events in cell adhesion, recognition, and contact-mediated inhibition of cell growth. Recently we reported that PS1 concentrates at cell-cell and synaptic contact sites where it incorporates into the cadherin/catenin cell-cell adhesion system. Here we present preliminary data that PS1 binds directly to E-cadherin and regulates Ca++-dependent cell-cell adhesion. In addition, our results indicate that PS1 and a gamma-secretase activity control production of a cadherin cytoplasmic peptide of about 20kDa (termed pC20) and regulate expression of both cyclin D1 and cyclin-dependent kinase inhibitor p27Kip1, two important cell cycle proteins. pC20 seems to be derived from a larger cadherin precursor termed pC35. pC35 is produced following an extracytoplasmic cleavage of the full length cadherin. Expression of a cadherin cytoplasmic peptide in PS1-deficient cells mimicked the pC20 effects and reduced the expression levels of both cyclin D1 and p27Kip1. Taken together, our preliminary data suggest that PS1, cadherins, and gamma-secretase are involved in a novel signal transduction mechanism that regulates expression of cell cycle proteins. This mechanism may use the cytoplasmic cadherin-derived peptide pC20 as a messenger which translocates to the nucleus where it controls expression of cell cycle proteins. PS1 and gamma-secretase activity may thus control the cadherin signal transduction pathway by regulating expression of the cadherin-derived message. This application proposes to characterize the cadherin-PS1-gamma-secretase signal transduction pathway and to examine its involvement in Alzheimer's disease.