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, 09:03 by Mhairi Morris, Louise Laverick, Wenbin Wei, Alexandra M. Davis, Samantha O'Neill, Liam Wood, Jack Wright, Christopher W. Dawson, Lawrence S. Young
© 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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