Document Detail


Differential regulation of growth-promoting signalling pathways by E-cadherin.
MedLine Citation:
PMID:  21049033     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Nikolaos T Georgopoulos; Lisa A Kirkwood; Dawn C Walker; Jennifer Southgate
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-10-26
Journal Detail:
Title:  PloS one     Volume:  5     ISSN:  1932-6203     ISO Abbreviation:  PLoS ONE     Publication Date:  2010  
Date Detail:
Created Date:  2010-11-04     Completed Date:  2011-03-07     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  101285081     Medline TA:  PLoS One     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e13621     Citation Subset:  IM    
Affiliation:
Jack Birch Unit for Molecular Carcinogenesis, Department of Biology, University of York, York, United Kingdom.
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MeSH Terms
Descriptor/Qualifier:
Cadherins / metabolism*
Cell Proliferation*
Cells, Cultured
Extracellular Signal-Regulated MAP Kinases / metabolism
Humans
Phosphatidylinositol 3-Kinases / metabolism
Proto-Oncogene Proteins c-akt / metabolism
Receptor, Epidermal Growth Factor / metabolism
Signal Transduction*
TCF Transcription Factors / metabolism
Urothelium / cytology,  enzymology,  metabolism
beta Catenin / metabolism
Chemical
Reg. No./Substance:
0/Cadherins; 0/TCF Transcription Factors; 0/beta Catenin; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.10.1/Receptor, Epidermal Growth Factor; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 2.7.11.24/Extracellular Signal-Regulated MAP Kinases
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