The Epstein-Barr virus protein, latent membrane protein 2A, co-opts tyrosine kinases used by the T cell receptor.
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.
Ingham
Robert J
RJ
Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
Raaijmakers
Judith
J
Lim
Caesar S H
CS
Mbamalu
Geraldine
G
Gish
Gerald
G
Chen
Fu
F
Matskova
Liudmila
L
Ernberg
Ingemar
I
Winberg
Gösta
G
Pawson
Tony
T
D000595:Amino Acid Sequence; D015536:Down-Regulation; D004854:Herpesvirus 4, Human / Q000737:chemistry*; D006801:Humans; D019169:Jurkat Cells; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D008969:Molecular Sequence Data; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000096:biosynthesis* / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics*; D014763:Viral Matrix Proteins / Q000235:genetics / Q000502:physiology*
C037662:EBV-associated membrane antigen, Epstein-Barr virus; D011948:Receptors, Antigen, T-Cell; D014763:Viral Matrix Proteins; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051076:Proto-Oncogene Proteins c-fyn