Differential Regulation of Growth-Promoting Signalling Pathways by E-Cadherin

Georgopoulos, Nikolaos T., Kirkwood, Lisa A., Walker, Dawn C. and Southgate, Jennifer (2010) Differential Regulation of Growth-Promoting Signalling Pathways by E-Cadherin. PLOS ONE. -. ISSN 1932-6203

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Abstract

Background: Despite the well-documented association between loss of E-cadherin and carcinogenesis, as well as the link between restoration of its expression and suppression of proliferation in carcinoma cells, the ability of E-cadherin to modulate growth-promoting cell signalling in normal epithelial cells is less well understood and frequently contradictory. The potential for E-cadherin to co-ordinate different proliferation-associated signalling pathways has yet to be fully explored. Methodology/Principal Findings: Using a normal human urothelial (NHU) cell culture system and following a calcium-switch approach, we demonstrate that the stability of NHU cell-cell contacts differentially regulates the Epidermal Growth Factor Receptor (EGFR)/Extracellular Signal-Regulated Kinase (ERK) and Phosphatidylinositol 3-Kinase (PI3-K)/AKT pathways. We show that stable cell contacts down-modulate the EGFR/ERK pathway, whilst inducing PI3-K/AKT activity, which transiently enhances cell growth at low density. Functional inactivation of E-cadherin interferes with the capacity of NHU cells to form stable calcium-mediated contacts, attenuates E-cadherin-mediated PI3-K/AKT induction and enhances NHU cell proliferation by allowing de-repression of the EGFR/ERK pathway and constitutive activation of beta-catenin-TCF signalling. Conclusions/Significance: Our findings provide evidence that E-cadherin can differentially and concurrently regulate specific growth-related signalling pathways in a context-specific fashion, with direct, functional consequences for cell proliferation and population growth. Our observations not only reveal a novel, complex role for E-cadherin in normal epithelial cell homeostasis and tissue regeneration, but also provide the basis for a more complete understanding of the consequences of E-cadherin loss on malignant transformation.

Item Type:	Article
Copyright, Publisher and Additional Information:	© 2010 Georgopoulos et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords:	HUMAN UROTHELIAL CELLS, LIGAND-INDEPENDENT ACTIVATION, HUMAN EPIDERMAL-KERATINOCYTES, FACTOR RECEPTOR, BLADDER-CANCER, IN-VITRO, PROTEIN-KINASE, TERMINAL DIFFERENTIATION, CARCINOMA-CELLS, ADHESION
Academic Units:	The University of York > Biology (York) The University of York > Biology (York) > Jack Birch Unit for Molecular Carcinogenesis (York)
Depositing User:	Miss Anthea Tucker
Date Deposited:	22 Nov 2010 10:02
Last Modified:	23 Apr 2013 23:01
Published Version:	http://dx.doi.org/10.1371/journal.pone.0013621
Status:	Published
Refereed:	Yes
Related URLs:	http://dx.doi.org/10.1371/journal.pone.0...
URI:	http://eprints.whiterose.ac.uk/id/eprint/42663

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