The Epstein-Barr Virus Protein, Latent Membrane Protein 2A, Co-opts Tyrosine Kinases Used by the T Cell Receptor

• Published in: The Journal of biological chemistry 2005-10, Vol.280 (40), p.34133-34142
• Main Authors: Ingham, Robert J., Raaijmakers, Judith, Lim, Caesar S.H., Mbamalu, Geraldine, Gish, Gerald, Chen, Fu, Matskova, Liudmila, Ernberg, Ingemar, Winberg, Gösta, Pawson, Tony
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Down-Regulation; Epstein-Barr virus; Herpesvirus 4, Human - chemistry; Humans; Jurkat Cells; Lymphocyte Specific Protein Tyrosine Kinase p56(lck) - metabolism; Molecular Sequence Data; Proto-Oncogene Proteins c-fyn - metabolism; Receptors, Antigen, T-Cell - biosynthesis; Receptors, Antigen, T-Cell - physiology; Signal Transduction - genetics; Viral Matrix Proteins - genetics; Viral Matrix Proteins - physiology
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M507831200

Epstein-Barr virus (EBV) is the causative agent of infectious mononucleosis and is associated with several human malignancies. The EBV protein latent membrane protein 2A (LMP2A) promotes viral latency in memory B cells by interfering with B cell receptor signaling and provides a survival signal for mature B cells that have lost expression of surface immunoglobulin. The latter function has suggested that LMP2A may enhance the survival of EBV-positive tumors. EBV is associated with several T cell malignancies and, since LMP2A has been detected in several of these disorders, we examined the ability of LMP2A to transmit signals and interfere with T cell receptor signaling in T cells. We show that LMP2A is tyrosine-phosphorylated in Jurkat TAg T cells, which requires expression of the Src family tyrosine kinases, Lck and Fyn. Lck and Fyn are recruited to the tyrosine-phosphorylated Tyr112 site in LMP2A, whereas phosphorylation of an ITAM motif in LMP2A creates a binding site for the ZAP-70/Syk tyrosine kinases. LMP2A also associates through its two PPPPY motifs with AIP4, a NEDD4 family E3 ubiquitin ligase; this interaction results in ubiquitylation of LMP2A and serves to regulate the stability of LMP2A and LMP2A-kinase complexes. Furthermore, stable expression of LMP2A in Jurkat T cells down-regulated T cell receptor levels and attenuated T cell receptor signaling. Thus, through recruiting tyrosine kinases involved in T cell receptor activation, LMP2A may provide a survival signal for EBV-positive T cell tumors, whereas LMP2A-associated NEDD4 E3 ligases probably titer the strength of this signal.