The EBV-encoded oncoprotein, LMP1, induces an epithelial-to-mesenchymal transition (EMT) via its CTAR1 domain through integrin-mediated ERK-MAPK signalling
journal contributionposted on 11.06.2018 by Mhairi Morris, Louise Laverick, Wenbin Wei, Alexandra M. Davis, Samantha O'Neill, Liam Wood, Jack Wright, Christopher W. Dawson, Lawrence S. Young
Any type of content formally published in an academic journal, usually following a peer-review process.
© 2018 by the authors. Licensee MDPI, Basel, Switzerland. The Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) oncogene can induce profound effects on epithelial growth and differentiation including many of the features of the epithelial-to-mesenchymal transition (EMT). To better characterise these effects, we used the well-defined Madin Darby Canine Kidney (MDCK) epithelial cell model and found that LMP1 expression in these cells induces EMT as defined by characteristic morphological changes accompanied by loss of E-cadherin, desmosomal cadherin and tight junction protein expression. The induction of the EMT phenotype required a functional CTAR1 domain of LMP1 and studies using pharmacological inhibitors revealed contributions from signalling pathways commonly induced by integrin-ligand interactions: extracellular signal-regulated kinases/mitogen-activated protein kinases (ERK-MAPK), PI3-Kinase and tyrosine kinases, but not transforming growth factor beta (TGF β). More detailed analysis implicated the CTAR1-mediated induction of Slug and Twist in LMP1-induced EMT. A key role for β1 integrin signalling in LMP1-mediated ERK-MAPK and focal adhesion kianse (FAK) phosphorylation was observed, and β1 integrin activation was found to enhance LMP1-induced cell viability and survival. These findings support an important role for LMP1 in disease pathogenesis through transcriptional reprogramming that enhances tumour cell survival and leads to a more invasive, metastatic phenotype.
The study was core funded by Cancer Research UK at the University of Birmingham.
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