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Journal of Virology, June 1999, p. 4767-4775, Vol. 73, No. 6
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Epithelial Cell Adhesion to Extracellular Matrix Proteins Induces Tyrosine Phosphorylation of the Epstein-Barr Virus Latent Membrane Protein 2: a Role for C-Terminal Src Kinase

Frank Scholle,1 Richard Longnecker,2 and Nancy Raab-Traub1,3,*

Department of Microbiology and Immunology1 and Lineberger Comprehensive Cancer Center,3 University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-7295, and Department of Microbiology-Immunology, Northwestern University Medical School, Chicago, Illinois 606112

Received 4 December 1998/Accepted 12 March 1999

The Epstein-Barr virus (EBV) latent membrane protein 2 (LMP2) is expressed in latently EBV-infected B cells, where it forms patches in the plasma membrane and interferes with B-cell receptor signal transduction through dominant-negative effects on protein kinases. LMP2 transcripts are detected in nasopharyngeal carcinoma, an epithelial-cell malignancy. In this study the function of LMP2A in epithelial cells was investigated. LMP2A was found to coprecipitate with protein kinase activities and to become phosphorylated in in vitro kinase assays. Analysis of LMP2A deletion mutants demonstrated that tyrosines implicated in interacting with Src family kinase SH2 domains and the SH2 domain of Csk, as well as the LMP2A immunoreceptor tyrosine-based activation motif, are important for its phosphorylation in epithelial cells. LMP2A tyrosine phosphorylation was triggered by cell adhesion to extracellular-matrix (ECM) proteins. Src family kinases, whose involvement in cell-ECM signaling and LMP2A phosphorylation in B lymphocytes has been well established, were found not to be responsible for LMP2A phosphorylation in epithelial cells. Instead, coexpression of Csk, a negative Src regulator, and LMP2A led to an increase in LMP2A phosphorylation both in nonadherent cells and upon cell adhesion. Csk also phosphorylated LMP2A in vitro. These results suggest that LMP2A has a different role in epithelial cells, where it interacts with cell adhesion-initiated signaling pathways. Although tyrosine phosphorylation of LMP2A occurs in both cell types, different protein kinases seem to be used: Src family kinases in B lymphocytes and Csk in epithelial cells.

* Corresponding author. Mailing address: Lineberger Comprehensive Cancer Center, CB no. 7295, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7295. Phone: (919) 966-1701. Fax: (919) 966-9673. E-mail: nrt{at}med.unc.edu.

Journal of Virology, June 1999, p. 4767-4775, Vol. 73, No. 6
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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