p120 Catenin Recruits Cadherins to γ-Secretase and Inhibits Production of Aβ Peptide
p120 Catenin Recruits Cadherins to γ-Secretase and Inhibits Production of Aβ Peptide
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DOI：
10.1074/jbc.m806250200
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发表时间：
2009-01-23
影响因子：
4.8
通讯作者：
Robakis, Nikolaos K.
中科院分区：
文献类型：
--
作者：
Kouchi, Zen;Barthet, Gael;Robakis, Nikolaos K.
γ-分泌酶复合物切割许多跨膜蛋白，包括淀粉样前体蛋白、EphB和ErbB酪氨酸激酶受体、Notch 1受体和粘附因子。早老素1，γ-分泌酶的催化亚基，与钙粘蛋白/连环蛋白细胞-细胞粘附/通讯系统结合并促进钙粘蛋白加工（Georgakopoulos，A.，等人（1999）Mol. Cell 4，893-902; Marambaud，P.，等人（2002）EMBO J. 21，1948-1956），但γ-分泌酶和钙粘蛋白缔合的机制尚不清楚。在这里，我们报告说，p120连环蛋白（p120 ctn），钙粘蛋白-连环蛋白复合物的一个组成部分，招聘γ-分泌酶钙粘蛋白，从而刺激他们的加工，同时抑制生产A β肽和淀粉样前体蛋白胞内结构域。p120 ctn的这种功能依赖于p120 ctn-钙粘蛋白和p120 ctn-早老素1的结合，表明p120 ctn是桥接γ-分泌酶和钙粘蛋白-连环蛋白复合物的中心因子。我们的数据表明，p120 ctn是一个独特的正调节剂的γ-分泌酶加工的钙粘蛋白和淀粉样前体蛋白加工的负调节剂。此外，我们的数据表明，γ-分泌酶复合物的特定成员可用于招募不同的底物，不同的PS1序列需要APP和钙粘蛋白的加工。
The gamma-secretase complex cleaves many transmembrane proteins, including amyloid precursor protein, EphB and ErbB tyrosine kinase receptors, Notch1 receptors, and adhesion factors. Presenilin 1, the catalytic subunit of gamma-secretase, associates with the cadherin/catenin cell-cell adhesion/communication system and promotes cadherin processing (Georgakopoulos, A., et al. (1999) Mol. Cell 4, 893-902; Marambaud, P., et al. (2002) EMBO J. 21, 1948-1956), but the mechanism by which gamma-secretase and cadherins associate is unclear. Here we report that p120 catenin (p120ctn), a component of the cadherin-catenin complex, recruits gamma-secretase to cadherins, thus stimulating their processing while inhibiting production of A beta peptide and the amyloid precursor protein intracellular domain. This function of p120ctn depends on both p120ctn-cadherin and p120ctn-presenilin 1 binding, indicating that p120ctn is the central factor that bridges gamma-secretase and cadherin-catenin complexes. Our data show that p120ctn is a unique positive regulator of the gamma-secretase processing of cadherins and a negative regulator of the amyloid precursor protein processing. Furthermore, our data suggest that specific members of the gamma-secretase complex may be used to recruit different substrates and that distinct PS1 sequences are required for processing of APP and cadherins.