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EGFR-Mediated Carcinoma Cell Metastasis Mediated by Integrin αvβ5 Depends on Activation of c-Src and Cleavage of MUC1
Receptor tyrosine kinases and integrins play an essential role in tumor cell invasion and metastasis. We previously showed that EGF and other growth factors induce human carcinoma cell invasion and metastasis mediated by integrin αvβ5 that is prevented by Src blockade [1]. MUC1, a transmembrane glyc...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3346745/ https://www.ncbi.nlm.nih.gov/pubmed/22586492 http://dx.doi.org/10.1371/journal.pone.0036753 |
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author | Lau, Steven K. M. Shields, David J. Murphy, Eric A. Desgrosellier, Jay S. Anand, Sudarshan Huang, Miller Kato, Shumei Lim, Ssang-Taek Weis, Sara M. Stupack, Dwayne G. Schlaepfer, David D. Cheresh, David A. |
author_facet | Lau, Steven K. M. Shields, David J. Murphy, Eric A. Desgrosellier, Jay S. Anand, Sudarshan Huang, Miller Kato, Shumei Lim, Ssang-Taek Weis, Sara M. Stupack, Dwayne G. Schlaepfer, David D. Cheresh, David A. |
author_sort | Lau, Steven K. M. |
collection | PubMed |
description | Receptor tyrosine kinases and integrins play an essential role in tumor cell invasion and metastasis. We previously showed that EGF and other growth factors induce human carcinoma cell invasion and metastasis mediated by integrin αvβ5 that is prevented by Src blockade [1]. MUC1, a transmembrane glycoprotein, is expressed in most epithelial tumors as a heterodimer consisting of an extracellular and a transmembrane subunit. The MUC1 cytoplasmic domain of the transmembrane subunit (MUC1.CD) translocates to the nucleus where it promotes the transcription of a metastatic gene signature associated with epithelial to mesenchymal transition. Here, we demonstrate a requirement for MUC1 in carcinoma cell metastasis dependent on EGFR and Src without affecting primary tumor growth. EGF stimulates Src-dependent MUC1 cleavage and nuclear localization leading to the expression of genes linked to metastasis. Moreover, expression of MUC1.CD results in its nuclear localization and is sufficient for transcription of the metastatic gene signature and tumor cell metastasis. These results demonstrate that EGFR and Src activity contribute to carcinoma cell invasion and metastasis mediated by integrin αvβ5 in part by promoting proteolytic cleavage of MUC1 and highlight the ability of MUC1.CD to promote metastasis in a context-dependent manner. Our findings may have implications for the use and future design of targeted therapies in cancers known to express EGFR, Src, or MUC1. |
format | Online Article Text |
id | pubmed-3346745 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-33467452012-05-14 EGFR-Mediated Carcinoma Cell Metastasis Mediated by Integrin αvβ5 Depends on Activation of c-Src and Cleavage of MUC1 Lau, Steven K. M. Shields, David J. Murphy, Eric A. Desgrosellier, Jay S. Anand, Sudarshan Huang, Miller Kato, Shumei Lim, Ssang-Taek Weis, Sara M. Stupack, Dwayne G. Schlaepfer, David D. Cheresh, David A. PLoS One Research Article Receptor tyrosine kinases and integrins play an essential role in tumor cell invasion and metastasis. We previously showed that EGF and other growth factors induce human carcinoma cell invasion and metastasis mediated by integrin αvβ5 that is prevented by Src blockade [1]. MUC1, a transmembrane glycoprotein, is expressed in most epithelial tumors as a heterodimer consisting of an extracellular and a transmembrane subunit. The MUC1 cytoplasmic domain of the transmembrane subunit (MUC1.CD) translocates to the nucleus where it promotes the transcription of a metastatic gene signature associated with epithelial to mesenchymal transition. Here, we demonstrate a requirement for MUC1 in carcinoma cell metastasis dependent on EGFR and Src without affecting primary tumor growth. EGF stimulates Src-dependent MUC1 cleavage and nuclear localization leading to the expression of genes linked to metastasis. Moreover, expression of MUC1.CD results in its nuclear localization and is sufficient for transcription of the metastatic gene signature and tumor cell metastasis. These results demonstrate that EGFR and Src activity contribute to carcinoma cell invasion and metastasis mediated by integrin αvβ5 in part by promoting proteolytic cleavage of MUC1 and highlight the ability of MUC1.CD to promote metastasis in a context-dependent manner. Our findings may have implications for the use and future design of targeted therapies in cancers known to express EGFR, Src, or MUC1. Public Library of Science 2012-05-07 /pmc/articles/PMC3346745/ /pubmed/22586492 http://dx.doi.org/10.1371/journal.pone.0036753 Text en Lau et al. http://creativecommons.org/licenses/by/4.0/ 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 properly credited. |
spellingShingle | Research Article Lau, Steven K. M. Shields, David J. Murphy, Eric A. Desgrosellier, Jay S. Anand, Sudarshan Huang, Miller Kato, Shumei Lim, Ssang-Taek Weis, Sara M. Stupack, Dwayne G. Schlaepfer, David D. Cheresh, David A. EGFR-Mediated Carcinoma Cell Metastasis Mediated by Integrin αvβ5 Depends on Activation of c-Src and Cleavage of MUC1 |
title | EGFR-Mediated Carcinoma Cell Metastasis Mediated by Integrin αvβ5 Depends on Activation of c-Src and Cleavage of MUC1 |
title_full | EGFR-Mediated Carcinoma Cell Metastasis Mediated by Integrin αvβ5 Depends on Activation of c-Src and Cleavage of MUC1 |
title_fullStr | EGFR-Mediated Carcinoma Cell Metastasis Mediated by Integrin αvβ5 Depends on Activation of c-Src and Cleavage of MUC1 |
title_full_unstemmed | EGFR-Mediated Carcinoma Cell Metastasis Mediated by Integrin αvβ5 Depends on Activation of c-Src and Cleavage of MUC1 |
title_short | EGFR-Mediated Carcinoma Cell Metastasis Mediated by Integrin αvβ5 Depends on Activation of c-Src and Cleavage of MUC1 |
title_sort | egfr-mediated carcinoma cell metastasis mediated by integrin αvβ5 depends on activation of c-src and cleavage of muc1 |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3346745/ https://www.ncbi.nlm.nih.gov/pubmed/22586492 http://dx.doi.org/10.1371/journal.pone.0036753 |
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