Presenilin 1 Regulates Epidermal Growth Factor Receptor Turnover and Signaling in the Endosomal-Lysosomal Pathway

Emanuela Repetto,Il-Sang Yoon,Hui Zheng,David E Kang

doi:10.1074/jbc.m704273200

Abstract

Mutations in the gene encoding presenilin 1 (PS1) cause the most aggressive form of early-onset familial Alzheimer disease. In addition to its well established role in Abeta production and Notch proteolysis, PS1 has been shown to mediate other physiological activities, such as regulation of the Wnt/beta-catenin signaling pathway, modulation of phosphatidylinositol 3-kinase/Akt and MEK/ERK signaling, and trafficking of select membrane proteins and/or intracellular vesicles. In this study, we present evidence that PS1 is a critical regulator of a key signaling receptor tyrosine kinase, epidermal growth factor receptor (EGFR). Specifically, EGFR levels were robustly increased in fibroblasts deficient in both PS1 and PS2 (PS(-/-)) due to delayed turnover of EGFR protein. Stable transfection of wild-type PS1 but not PS2 corrected EGFR to levels comparable to PS(+/+) cells, while FAD PS1 mutations showed partial loss of activity. The C-terminal fragment of PS1 was sufficient to fully reduce EGFR levels. In addition, the rapid ligand-induced degradation of EGFR was markedly delayed in PS(-/-) cells, resulting in prolonged signal activation. Despite the defective turnover of EGFR, ligand-induced autophosphorylation, ubiquitination, and endocytosis of EGFR were not affected by the lack of PS1. Instead, the trafficking of EGFR from early endosomes to lysosomes was severely delayed by PS1 deficiency. Elevation of EGFR was also seen in brains of adult mice conditionally ablated in PS1 and in skin tumors associated with the loss of PS1. These findings demonstrate a critical role of PS1 in the trafficking and turnover of EGFR and suggest potential pathogenic effects of elevated EGFR as well as perturbed endosomal-lysosomal trafficking in cell cycle control and Alzheimer disease.

Highlights

Alzheimer disease (FAD) [1, 2]
Presenilin 1 Deficiency Dramatically Elevates EGF Receptor Levels by Reduced Turnover at Steady State—We previously showed that PDGFR levels were reduced in PSϪ/Ϫ fibroblasts that are genetically deficient in both presenilin 1 (PS1) and presenilin 2 (PS2), a phenotype that was rescued by reintroduction of PS2 but not PS1 [11]
We previously showed that EGF-induced Akt and ERK1/2 phosphorylation was largely normal in PSϪ/Ϫ cells up to 1-h of exposure, we had not performed an exhaustive study of epidermal growth factor receptor (EGFR) levels and downstream signaling events [11]

Summary

Introduction

Alzheimer disease (FAD) [1, 2]. Presenilins are multipass transmembrane proteins that form the core enzymatic activity of the ␥-secretase complex together with nicastrin, pen-2, and aph-1. We previously showed that EGF-induced Akt and ERK1/2 phosphorylation was largely normal in PSϪ/Ϫ cells up to 1-h of exposure, we had not performed an exhaustive study of EGFR levels and downstream signaling events [11].

Results

Conclusion