EGFR-Mediated Carcinoma Cell Metastasis Mediated by Integrin αvβ5 Depends on Activation of c-Src and Cleavage of MUC1

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

doi:10.1371/journal.pone.0036753

Steven K M Lau, Shumei Kato + Show 10 more

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https://doi.org/10.1371/journal.pone.0036753

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Journal: PloS one	Publication Date: May 7, 2012
Citations: 89	License type: CC BY 4.0

Affiliation: University of California, San Diego

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.

Highlights

Epithelial tumor cell metastasis is the culmination of multiple steps including remodeling and invasion of the extracellular matrix [2]
Since cross-talk between receptor tyrosine kinases and integrins regulates the metastatic capacity of various human cancers [3], characterization of the molecular mechanisms resulting from this cross-talk is essential to understanding metastasis
We have identified signaling events coordinated by EGFR and integrin avb5 that regulate the invasive behavior of human carcinoma cells

Summary

Introduction

Epithelial tumor cell metastasis is the culmination of multiple steps including remodeling and invasion of the extracellular matrix [2]. We have identified signaling events that are coordinated by epidermal growth factor (EGF) and a specific integrin to regulate the invasive behavior of human carcinoma cells. A growing body of literature has revealed that cooperative signaling between receptor tyrosine kinases and integrins regulates cell adhesion, migration, invasion, and survival [3]. We previously reported that integrin avb, in the absence of growth factor stimulation, is unable to form focal adhesions and initiate cell migration/invasion [5]. Cell invasion mediated by b1 integrins occurs independent of EGF [6,7] and Src activity [1]. Understanding how EGFR and Src regulate avb5-mediated tumor cell metastasis could lead to novel therapeutic strategies to prevent the metastatic spread of human cancers

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