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Secretion of protein disulphide isomerase AGR2 confers tumorigenic properties

Journal article
Authors D. Fessart
C. Domblides
T. Avril
Leif A Eriksson
H. Begueret
R. Pineau
C. Malrieux
N. Dugot-Senant
C. Lucchesi
E. Chevet
F. Delom
Published in Elife
Volume 5
ISSN 2050-084X
Publication year 2016
Published at Department of Chemistry and Molecular Biology
Language en
Links dx.doi.org/10.7554/eLife.13887
Keywords EPITHELIAL-MESENCHYMAL TRANSITION, EXTRACELLULAR-MATRIX, ANTERIOR, GRADIENT-2, CELL-PROLIFERATION, PANCREATIC-CANCER, METASTASIS, LOCALIZATION, MIGRATION, SURVIVAL, TISSUE
Subject categories Biochemistry and Molecular Biology

Abstract

The extracellular matrix (ECM) plays an instrumental role in determining the spatial orientation of epithelial polarity and the formation of lumens in glandular tissues during morphogenesis. Here, we show that the Endoplasmic Reticulum (ER)-resident protein anterior gradient-2 (AGR2), a soluble protein-disulfide isomerase involved in ER protein folding and quality control, is secreted and interacts with the ECM. Extracellular AGR2 (eAGR2) is a microenvironmental regulator of epithelial tissue architecture, which plays a role in the preneoplastic phenotype and contributes to epithelial tumorigenicity. Indeed, eAGR2, is secreted as a functionally active protein independently of its thioredoxin-like domain (CXXS) and of its ER retention domain (KTEL), and is sufficient, by itself, to promote the acquisition of invasive and metastatic features. Therefore, we conclude that eAGR2 plays an extracellular role independent of its ER function and we elucidate this gain-of-function as a novel and unexpected critical ECM microenvironmental pro-oncogenic regulator of epithelial morphogenesis and tumorigenesis.

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