title: Epstein-Barr virus LMP1 activates EGFR, STAT3, and ERK through effects on PKCdelta.
abstract: Epstein-Barr virus (EBV) is a ubiquitous herpesvirus that infects more than 90% of the world's adult population and is linked to multiple malignancies, including Burkitt lymphoma, Hodgkin disease, and nasopharyngeal carcinoma (NPC). The EBV oncoprotein LMP1 induces transcription of the epidermal growth factor receptor (EGFR), which is expressed at high levels in NPC. EGFR transcription is induced by LMP1 through a p50 NFκB1-Bcl-3 complex, and Bcl-3 is induced by LMP1-mediated activation of STAT3. This study reveals that LMP1, through its carboxyl-terminal activation domain 1 (LMP1-CTAR1), activates both STAT3 and EGFR in a serum-independent manner with constitutive serine phosphorylation of STAT3. Upon treatment with EGF, the LMP1-CTAR1-induced EGFR was additionally phosphorylated and STAT3 became phosphorylated on tyrosine, concomitant with upregulation of a subset of STAT3 target genes. The kinase responsible for LMP1-CTAR1-mediated serine phosphorylation of STAT3 was identified to be PKCδ using specific RNAi, a dominant negative PKCδ, and the PKCδ inhibitor rottlerin. Interestingly, inhibition of PKCδ also inhibited constitutive phosphorylation of EGFR and LMP1-CTAR1-induced phosphorylation of ERK. Inhibition of PKCδ blocked LMP1-CTAR1-mediated transformation of Rat-1 cells, likely through the inhibition of ERK activation. These findings indicate that LMP1 activates multiple distinct signaling pathways and suggest that PKCδ functions as a master regulator of EGFR, STAT3, and ERK activation by LMP1-CTAR1.
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
authors.forename: Che-Pei
authors.initials: CP
authors.lastname: Kung
authors.forename: David G
authors.initials: DG
authors.lastname: Meckes
authors.forename: Nancy
authors.initials: N
authors.lastname: Raab-Traub
mesh_terms: D000818:Animals; D002460:Cell Line; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D004854:Herpesvirus 4, Human / Q000472:pathogenicity*; D054884:Host-Pathogen Interactions; D006801:Humans; D051745:Protein Kinase C-delta / Q000378:metabolism*; D051381:Rats; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014763:Viral Matrix Proteins / Q000378:metabolism*
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014763:Viral Matrix Proteins; C512478:EGFR protein, human; D066246:ErbB Receptors; D051745:Protein Kinase C-delta; D048049:Extracellular Signal-Regulated MAP Kinases