P120 Catenin Recruits Cadherins to γ-Secretase and Inhibits Production of Aβ Peptide

Zen Kouchi,Gael Barthet,Geo Serban,Anastasios Georgakopoulos,Junichi Shioi,Nikolaos K Robakis

doi:10.1074/jbc.m806250200

Zen Kouchi, Gael Barthet + Show 4 more

Open Access

https://doi.org/10.1074/jbc.m806250200

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Abstract

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 Abeta 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.

Highlights

Presenilin 1 (PS1)6 is a multipass transmembrane protein involved in most cases of early-onset familial Alzheimer disease
The ⑀ cleavages occur close to the membrane/cytoplasm interface and promote the production of soluble peptides containing the cytoplasmic C-terminal sequence of the cleaved proteins (CTFs). Many of these peptides have been shown to function as transcription factors and cell surface-to-nucleus communication signals. In agreement with this function of the ␥-secretase proteolytic complex, PS1 is found at the plasma membrane in cell-cell contact sites where it associates with the cadherin-catenin adherens junctions [1]
The p120ctncatenin family contains 10 –12 armadillo repeats [13], and in contrast to ␤- and ␥-catenins that bind the distal sequence of cytosolic cadherins, members of the p120ctn family bind directly to the juxtamembrane sequence of cadherins and regulate their stability [14, 15]. p120ctn itself regulates the activity of the Rho family of GTPases [16] and promotes gene expression by binding transcription factor Kaiso and regulating its DNA-binding activity [17, 18]

Summary

Introduction

Presenilin 1 (PS1) is a multipass transmembrane protein involved in most cases of early-onset familial Alzheimer disease. The ⑀ cleavages occur close to the membrane/cytoplasm interface and promote the production of soluble peptides containing the cytoplasmic C-terminal sequence of the cleaved proteins (CTFs) Many of these peptides have been shown to function as transcription factors and cell surface-to-nucleus communication signals (for review, see Ref. 7). In agreement with this function of the ␥-secretase proteolytic complex, PS1 is found at the plasma membrane in cell-cell contact sites where it associates with the cadherin-catenin adherens junctions [1]. P120ctn suppresses APP processing and A␤ production, possibly by recruiting ␥-secretase to cadherins and limiting its availability for the processing of APP

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