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

Nikolaos T. Georgopoulos, Lisa A. Kirkwood, Dawn C. Walker, Jennifer Southgate

Research output: Contribution to journalArticle

24 Citations (Scopus)

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 β-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.

Original languageEnglish
Article numbere13621
Number of pages12
JournalPLoS One
Volume5
Issue number10
DOIs
Publication statusPublished - 26 Oct 2010

Fingerprint

cadherins
Cadherins
Phosphatidylinositol 3-Kinase
Growth
Extracellular Signal-Regulated MAP Kinases
phosphatidylinositol 3-kinase
mitogen-activated protein kinase
Epidermal Growth Factor Receptor
Cell proliferation
cells
cell proliferation
epithelial cells
Epithelial Cells
Cell Proliferation
Cell signaling
Calcium
calcium
Catenins
Tissue regeneration
Population Growth

Cite this

Georgopoulos, Nikolaos T. ; Kirkwood, Lisa A. ; Walker, Dawn C. ; Southgate, Jennifer. / Differential Regulation of Growth-Promoting Signalling Pathways by E-Cadherin. In: PLoS One. 2010 ; Vol. 5, No. 10.
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Differential Regulation of Growth-Promoting Signalling Pathways by E-Cadherin. / Georgopoulos, Nikolaos T.; Kirkwood, Lisa A.; Walker, Dawn C.; Southgate, Jennifer.

In: PLoS One, Vol. 5, No. 10, e13621, 26.10.2010.

Research output: Contribution to journalArticle

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T1 - Differential Regulation of Growth-Promoting Signalling Pathways by E-Cadherin

AU - Georgopoulos, Nikolaos T.

AU - Kirkwood, Lisa A.

AU - Walker, Dawn C.

AU - Southgate, Jennifer

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