title: Epstein-Barr virus latent membrane protein 1 (LMP1) activates the phosphatidylinositol 3-kinase/Akt pathway to promote cell survival and induce actin filament remodeling.
abstract: The Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) is an integral membrane protein that functions as a constitutively activated member of the tumor necrosis factor receptor family. Whereas LMP1 has been shown to activate the NF-kappaB and mitogen-activated protein kinase pathways, these effects alone are unable to account for the profound oncogenic properties of LMP1. Here we show that LMP1 can activate phosphatidylinositol 3-kinase (PI3K), a lipid kinase responsible for activating a diverse range of cellular processes in response to extracellular stimuli. LMP1 was found to stimulate PI3K activity inducing phosphorylation and subsequent activation of Akt, a downstream target of PI3K responsible for promoting cell survival. Treatment of LMP1-expressing cells with the PI3K inhibitor LY294002 resulted in decreased cell survival. The tumor necrosis factor receptor-associated factor-binding domain of LMP1 was found to be responsible for PI3K activation. The ability of LMP1 to induce actin stress-fiber formation, a Rho GTPase-mediated phenomenon, was also dependent on PI3K activation. These data implicate PI3K activation in many of the LMP1-induced phenotypic effects associated with transformation and suggests that this pathway contributes both to the oncogenicity of this molecule and its role in the establishment of persistent EBV infection.
authors.affiliation: Cancer Research UK Institute for Cancer Studies, The University of Birmingham Medical School, United Kingdom.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Dawson
authors.forename: Giorgos
authors.initials: G
authors.lastname: Tramountanis
authors.forename: Aristides G
authors.initials: AG
authors.lastname: Eliopoulos
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Young
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology*; D002472:Cell Transformation, Viral; D002867:Chromones / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020558:GTP Phosphohydrolases / Q000378:metabolism; D004854:Herpesvirus 4, Human / Q000502:physiology*; D009025:Morpholines / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D014763:Viral Matrix Proteins / Q000737:chemistry / Q000502:physiology*
chemical_list: D000199:Actins; D002867:Chromones; D004791:Enzyme Inhibitors; D020558:GTP Phosphohydrolases; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D014763:Viral Matrix Proteins; C037662:EBV-associated membrane antigen, Epstein-Barr virus; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C494920:Akt1 protein, rat