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J. Biol. Chem., Vol. 280, Issue 40, 34133-34142, October 7, 2005

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

Robert J. Ingham1, Judith Raaijmakers, Caesar S. H. Lim, Geraldine Mbamalu, Gerald Gish, Fu Chen¶, Liudmila Matskova¶2, Ingemar Ernberg¶, Gösta Winberg¶2, and Tony Pawson3

From the Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada, ^¶Karolinska Institutet, Microbiology and Tumor Biology Center, Stockholm SE-171 77, Sweden, and the Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada

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.

Received for publication, July 19, 2005

^* This work was supported by grants from the Canadian Institutes for Health Research (to T. P.) and the Swedish Cancer Society (to I. E.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipient of a postdoctoral fellowship from the National Cancer Institute of Canada (supported by Funds from the Terry Fox Run) and a Fellow of the Leukemia and Lymphoma Society. Present address: Dept. of Biology, University of Victoria, Petch Bldg. 053, 3800 Finnerty Rd., Victoria, British Columbia V8P 5C2, Canada.

² Recipient of Swedish Research Council Grant K2002-16X-14227-01A and Swedish Children's Cancer Foundation Grant PROJ01/18.

³ To whom correspondence should be addressed: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 600 University Ave., Toronto, Ontario M5G 1X5, Canada. Tel.: 416-586-4524; Fax: 416-586-8869; E-mail: pawson{at}mshri.on.ca.

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