Journal article
Epstein-Barr Virus Latent Membrane Protein 2A Activates β-Catenin Signaling in Epithelial Cells
Journal of virology, Vol.77(22), pp.12276-12284
11/2003
DOI: 10.1128/JVI.77.22.12276-12284.2003
PMCID: PMC254275
PMID: 14581564
Abstract
The Epstein-Barr virus (EBV) latent membrane protein 2A (LMP2A) functions to maintain latency in EBV-infected B lymphocytes. Although LMP2A is nonessential for the immortalization of B lymphocytes by EBV, its expression in B lymphocytes prevents viral reactivation by blocking B-cell receptor activation and signaling. LMP2A also provides an antiapoptotic signal in transgenic mice that express LMP2A in B lymphocytes. LMP2A activates phosphatidylinositol 3-kinase (PI3K) and the serine/threonine kinase Akt in lymphocytes and epithelial cells. Here we show that EBV LMP2A activates the PI3K and β-catenin signaling pathways in telomerase-immortalized human foreskin keratinocytes (HFK). LMP2A activated Akt in a PI3K-dependent manner, and the downstream Akt targets glycogen synthase kinase 3β (GSK3β) and the Forkhead transcription factor FKHR were phosphorylated and inactivated in LMP2A-expressing HFK cells. GSK3β is a negative regulator of the Wnt signaling pathway, and inactivation of GSK3β by LMP2A signaling led to stabilization of β-catenin, the central oncoprotein of Wnt signaling. In LMP2A-expressing cells, β-catenin accumulated in the cytoplasm and translocated into the nucleus via a two-step mechanism. The cytoplasmic accumulation of β-catenin downstream of LMP2A was independent of PI3K signaling, whereas its nuclear translocation was dependent on PI3K signaling. In the nucleus, β-catenin activated a reporter responsive to T-cell factor, and this activation was augmented by LMP2A coexpression. The Wnt pathway is inappropriately activated in 90% of colon cancers and is dysregulated in several other cancers, and these data suggest that activation of this pathway by LMP2A may contribute to the generation of EBV-associated cancers.
Details
- Title: Subtitle
- Epstein-Barr Virus Latent Membrane Protein 2A Activates β-Catenin Signaling in Epithelial Cells
- Creators
- J. A Morrison - Department of Microbiology, University of Iowa, Iowa City, Iowa 52242A. J Klingelhutz - Department of Microbiology, University of Iowa, Iowa City, Iowa 52242N Raab-Traub - Department of Microbiology, University of Iowa, Iowa City, Iowa 52242
- Resource Type
- Journal article
- Publication Details
- Journal of virology, Vol.77(22), pp.12276-12284
- DOI
- 10.1128/JVI.77.22.12276-12284.2003
- PMID
- 14581564
- PMCID
- PMC254275
- NLM abbreviation
- J Virol
- ISSN
- 0022-538X
- eISSN
- 1098-5514
- Publisher
- American Society for Microbiology
- Language
- English
- Date published
- 11/2003
- Academic Unit
- Microbiology and Immunology; Radiation Oncology
- Record Identifier
- 9984002378102771
Metrics
20 Record Views