title: The Epstein-Barr virus encoded LMP1 oncoprotein modulates cell adhesion via regulation of activin A/TGFβ and β1 integrin signalling.
abstract: Approximately 20% of global cancer incidence is causally linked to an infectious agent. Epstein-Barr virus (EBV) accounts for around 1% of all virus-associated cancers and is associated with nasopharyngeal carcinoma (NPC). Latent membrane protein 1 (LMP1), the major oncoprotein encoded by EBV, behaves as a constitutively active tumour necrosis factor (TNF) receptor activating a variety of signalling pathways, including the three classic MAPKs (ERK-MAPK, p38 MAPK and JNK/SAPK). The present study identifies novel signalling properties for this integral membrane protein via the induction and secretion of activin A and TGFβ1, which are both required for LMP1's ability to induce the expression of the extracellular matrix protein, fibronectin. However, it is evident that LMP1 is unable to activate the classic Smad-dependent TGFβ signalling pathway, but rather elicits its effects through the non-Smad arm of TGFβ signalling. In addition, there is a requirement for JNK/SAPK signalling in LMP1-mediated fibronectin induction. LMP1 also induces the expression and activation of the major fibronectin receptor, α5β1 integrin, an effect that is accompanied by increased focal adhesion formation and turnover. Taken together, these findings support the putative role for LMP1 in the pathogenesis of NPC by contributing to the metastatic potential of epithelial cells.
authors.affiliation: Faculty of Health and Life Sciences, Hawthorn Building, De Montfort University, The Gateway, Leicester, LE1 9BH.
authors.forename: Mhairi A
authors.initials: MA
authors.lastname: Morris
authors.affiliation: Institute for Cancer Studies, School of Cancer Sciences, The University of Birmingham, Vincent Drive, Edgbaston, Birmingham, B15 2TT.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Dawson
authors.affiliation: Department of Medicine, University of Melbourne, Clinical Sciences, Royal Melbourne Hospital, Royal Parade, Parkville, Victoria 3050.
authors.forename: Louise
authors.initials: L
authors.lastname: Laverick
authors.affiliation: Faculty of Health and Life Sciences, Hawthorn Building, De Montfort University, The Gateway, Leicester, LE1 9BH.
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Davis
authors.affiliation: Faculty of Health and Life Sciences, Hawthorn Building, De Montfort University, The Gateway, Leicester, LE1 9BH.
authors.forename: Joe P R
authors.initials: JP
authors.lastname: Dudman
authors.affiliation: Faculty of Health and Life Sciences, Hawthorn Building, De Montfort University, The Gateway, Leicester, LE1 9BH.
authors.forename: Sathuwarman
authors.initials: S
authors.lastname: Raveenthiraraj
authors.affiliation: Faculty of Health and Life Sciences, Hawthorn Building, De Montfort University, The Gateway, Leicester, LE1 9BH.
authors.forename: Zeeshan
authors.initials: Z
authors.lastname: Ahmad
authors.affiliation: Department of Oral Biology &Biomedical Sciences and Oral Cancer Research &Coordinating Centre, Faculty of Dentistry, University of Malaya, 50603, Kuala Lumpur, Malaysia.
authors.forename: Lee-Fah
authors.initials: LF
authors.lastname: Yap
authors.affiliation: Warwick Medical School, University of Warwick, Coventry, CV4 8UW.
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Young
mesh_terms: D028341:Activins / Q000378:metabolism*; D002277:Carcinoma; D002448:Cell Adhesion / Q000502:physiology*; D002460:Cell Line; D004847:Epithelial Cells / Q000821:virology; D020031:Epstein-Barr Virus Infections / Q000821:virology; D004854:Herpesvirus 4, Human / Q000378:metabolism*; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000821:virology; D015513:Oncogene Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014763:Viral Matrix Proteins / Q000378:metabolism*
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; D019012:Integrin beta1; D015513:Oncogene Proteins; D016212:Transforming Growth Factor beta; D014763:Viral Matrix Proteins; C422405:activin A; D028341:Activins