Cadherin-PS1-gamma-secretase signal transduction pathway

钙粘蛋白-PS1-γ-分泌酶信号转导通路

• 批准号: 6789392
• 负责人: NIKOLAOS K ROBAKIS
• 金额: $ 40.26万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-08-01 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6789392
• 关键词: Alzheimer' s disease; biological signal transduction; cadherins; cell adhesion; cell cycle proteins; cell growth regulation; cyclin dependent kinase; cyclins; developmental neurobiology; endopeptidases; enzyme activity; enzyme inhibitors; flavin adenine dinucleotide; genetically modified animals; human tissue; immunologic assay /test; laboratory mouse; phosphorylation; presenilin; protein binding; protein protein interaction; protein structure function; tissue /cell culture

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.

Presenilin1 (PS1) 是一种多位整合膜蛋白，在家族性阿尔茨海默病 (FAD) 的发展中发挥重要作用。 经典钙粘蛋白是 I 型跨膜糖蛋白，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 集中在细胞与细胞和突触接触位点，在那里它融入钙粘蛋白/连环蛋白细胞-细胞粘附系统。 在这里，我们提供了 PS1 直接与 E-钙粘蛋白结合并调节 Ca++ 依赖性细胞间粘附的初步数据。 此外，我们的结果表明，PS1 和 γ 分泌酶活性控制约 20kDa 的钙粘蛋白胞质肽（称为 pC20）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 p27Kip1（两种重要的细胞周期蛋白）的表达。 pC20 似乎源自更大的钙粘蛋白前体，称为 pC35。 pC35 是在全长钙粘蛋白的胞质外裂解后产生的。 PS1 缺陷细胞中钙粘蛋白胞质肽的表达模拟了 pC20 效应，并降低了细胞周期蛋白 D1 和 p27Kip1 的表达水平。 综上所述，我们的初步数据表明，PS1、钙粘蛋白和γ-分泌酶参与了调节细胞周期蛋白表达的新型信号转导机制。 该机制可能使用细胞质钙粘蛋白衍生肽 pC20 作为易位至细胞核的信使，在细胞核中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。 本申请旨在表征钙粘蛋白-PS1-γ-分泌酶信号转导途径并检查其与阿尔茨海默病的关系。