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Initial activation of EpCAM cleavage via cell-to-cell contact

BACKGROUND: Epithelial cell adhesion molecule EpCAM is a transmembrane glycoprotein, which is frequently over-expressed in simple epithelia, progenitors, embryonic and tissue stem cells, carcinoma and cancer-initiating cells. Besides functioning as a homophilic adhesion protein, EpCAM is an oncogeni...

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Autores principales: Denzel, Sabine, Maetzel, Dorothea, Mack, Brigitte, Eggert, Carola, Bärr, Gabriele, Gires, Olivier
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2784796/
https://www.ncbi.nlm.nih.gov/pubmed/19925656
http://dx.doi.org/10.1186/1471-2407-9-402
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author Denzel, Sabine
Maetzel, Dorothea
Mack, Brigitte
Eggert, Carola
Bärr, Gabriele
Gires, Olivier
author_facet Denzel, Sabine
Maetzel, Dorothea
Mack, Brigitte
Eggert, Carola
Bärr, Gabriele
Gires, Olivier
author_sort Denzel, Sabine
collection PubMed
description BACKGROUND: Epithelial cell adhesion molecule EpCAM is a transmembrane glycoprotein, which is frequently over-expressed in simple epithelia, progenitors, embryonic and tissue stem cells, carcinoma and cancer-initiating cells. Besides functioning as a homophilic adhesion protein, EpCAM is an oncogenic receptor that requires regulated intramembrane proteolysis for activation of its signal transduction capacity. Upon cleavage, the extracellular domain EpEX is released as a soluble ligand while the intracellular domain EpICD translocates into the cytoplasm and eventually into the nucleus in combination with four-and-a-half LIM domains protein 2 (FHL2) and β-catenin, and drives cell proliferation. METHODS: EpCAM cleavage, induction of the target genes, and transmission of proliferation signals were investigated under varying density conditions using confocal laser scanning microscopy, immunoblotting, cell counting, and conditional cell systems. RESULTS: EpCAM cleavage, induction of the target genes, and transmission of proliferation signals were dependent on adequate cell-to-cell contact. If cell-to-cell contact was prohibited EpCAM did not provide growth advantages. If cells were allowed to undergo contact to each other, EpCAM transmitted proliferation signals based on signal transduction-related cleavage processes. Accordingly, the pre-cleaved version EpICD was not dependent on cell-to-cell contact in order to induce c-myc and cell proliferation, but necessitated nuclear translocation. For the case of contact-inhibited cells, although cleavage of EpCAM occurred, nuclear translocation of EpICD was reduced, as were EpCAM effects. CONCLUSION: Activation of EpCAM's cleavage and oncogenic capacity is dependent on cellular interaction (juxtacrine) to provide for initial signals of regulated intramembrane proteolysis, which then support signalling via soluble EpEX (paracrine).
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spelling pubmed-27847962009-11-28 Initial activation of EpCAM cleavage via cell-to-cell contact Denzel, Sabine Maetzel, Dorothea Mack, Brigitte Eggert, Carola Bärr, Gabriele Gires, Olivier BMC Cancer Research Article BACKGROUND: Epithelial cell adhesion molecule EpCAM is a transmembrane glycoprotein, which is frequently over-expressed in simple epithelia, progenitors, embryonic and tissue stem cells, carcinoma and cancer-initiating cells. Besides functioning as a homophilic adhesion protein, EpCAM is an oncogenic receptor that requires regulated intramembrane proteolysis for activation of its signal transduction capacity. Upon cleavage, the extracellular domain EpEX is released as a soluble ligand while the intracellular domain EpICD translocates into the cytoplasm and eventually into the nucleus in combination with four-and-a-half LIM domains protein 2 (FHL2) and β-catenin, and drives cell proliferation. METHODS: EpCAM cleavage, induction of the target genes, and transmission of proliferation signals were investigated under varying density conditions using confocal laser scanning microscopy, immunoblotting, cell counting, and conditional cell systems. RESULTS: EpCAM cleavage, induction of the target genes, and transmission of proliferation signals were dependent on adequate cell-to-cell contact. If cell-to-cell contact was prohibited EpCAM did not provide growth advantages. If cells were allowed to undergo contact to each other, EpCAM transmitted proliferation signals based on signal transduction-related cleavage processes. Accordingly, the pre-cleaved version EpICD was not dependent on cell-to-cell contact in order to induce c-myc and cell proliferation, but necessitated nuclear translocation. For the case of contact-inhibited cells, although cleavage of EpCAM occurred, nuclear translocation of EpICD was reduced, as were EpCAM effects. CONCLUSION: Activation of EpCAM's cleavage and oncogenic capacity is dependent on cellular interaction (juxtacrine) to provide for initial signals of regulated intramembrane proteolysis, which then support signalling via soluble EpEX (paracrine). BioMed Central 2009-11-19 /pmc/articles/PMC2784796/ /pubmed/19925656 http://dx.doi.org/10.1186/1471-2407-9-402 Text en Copyright ©2009 Denzel et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Denzel, Sabine
Maetzel, Dorothea
Mack, Brigitte
Eggert, Carola
Bärr, Gabriele
Gires, Olivier
Initial activation of EpCAM cleavage via cell-to-cell contact
title Initial activation of EpCAM cleavage via cell-to-cell contact
title_full Initial activation of EpCAM cleavage via cell-to-cell contact
title_fullStr Initial activation of EpCAM cleavage via cell-to-cell contact
title_full_unstemmed Initial activation of EpCAM cleavage via cell-to-cell contact
title_short Initial activation of EpCAM cleavage via cell-to-cell contact
title_sort initial activation of epcam cleavage via cell-to-cell contact
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2784796/
https://www.ncbi.nlm.nih.gov/pubmed/19925656
http://dx.doi.org/10.1186/1471-2407-9-402
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