EGFR-mediated carcinoma cell metastasis mediated by integrin αvβ5 depends on activation of c-Src and cleavage of MUC1

Steven K M Lau, David J. Shields, Eric A. Murphy, Jay S. Desgrosellier, Sudarshan Anand, Miller Huang, Shumei Kato, Ssang Taek Lim, Sara M. Weis, Dwayne G. Stupack, David D. Schlaepfer, David A. Cheresh

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numbere36753
JournalPLoS One
Volume7
Issue number5
DOIs
StatePublished - May 7 2012
Externally publishedYes

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integrins
Integrins
metastasis
carcinoma
Chemical activation
Cells
Tumors
Neoplasm Metastasis
Carcinoma
cell invasion
Genes
Transcription
Epidermal Growth Factor
cells
Neoplasms
neoplasms
transcription (genetics)
Receptor Protein-Tyrosine Kinases
Epithelial-Mesenchymal Transition
Intercellular Signaling Peptides and Proteins

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Lau, S. K. M., Shields, D. J., Murphy, E. A., Desgrosellier, J. S., Anand, S., Huang, M., ... Cheresh, D. A. (2012). EGFR-mediated carcinoma cell metastasis mediated by integrin αvβ5 depends on activation of c-Src and cleavage of MUC1. PLoS One, 7(5), [e36753]. https://doi.org/10.1371/journal.pone.0036753

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.

In: PLoS One, Vol. 7, No. 5, e36753, 07.05.2012.

Research output: Contribution to journalArticle

Lau, SKM, Shields, DJ, Murphy, EA, Desgrosellier, JS, Anand, S, Huang, M, Kato, S, Lim, ST, Weis, SM, Stupack, DG, Schlaepfer, DD & Cheresh, DA 2012, 'EGFR-mediated carcinoma cell metastasis mediated by integrin αvβ5 depends on activation of c-Src and cleavage of MUC1', PLoS One, vol. 7, no. 5, e36753. https://doi.org/10.1371/journal.pone.0036753
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. In: PLoS One. 2012 ; Vol. 7, No. 5.
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