Integral membrane protein 2 of Epstein—barr virus regulates reactivation from latency through dominant negative effects on protein-tyrosine kinases

Abstract

An Epstein-Barr virus-encoded protein, LMP2, blocks the effects of surface immunoglobulin (slg) cross-linking on calcium mobilization and on lytic reactivation of EBV in latently infected and growth-transformed primary human B lymphocytes. In wild-type EBV-transformed cells, LMP2 is constitutively tyrosine phosphorylated and is associated with Lyn and Syk protein-tyrosine kinases (PTKs). Baseline Lyn PTK activity is substantially reduced, and slg cross-linking fails to activate Lyn, Syk, Pl3-K, PLC gamma 2, Vav, Shc, and MAPK. Syk, Pl3-K, PLC gamma 2, and Vav are constitutively tyrosine phosphorylated, and their tyrosine phosphorylation does not change following slg cross-linking. In contrast, cross-linking slg on cells transformed by LMP2 null mutant EBV recombinants triggers the same protein tyrosine kinase cascade as in noninfected B lymphocytes. These data are consistent with a model in which LMP2 is a constitutive dominant negative modulator of slg receptor signaling through its effects on Lyn, Syk, or regulators of these kinases.

Current understanding of the role of Epstein–Barr virus in lymphomagenesis and therapeutic approaches to EBV-associated lymphomas

“…The nuclear factor (NF)-κB signaling cascade is also activated by LMP1 [Thorley-Lawson 2001]. The other LMP, LMP2, prevents reactivation of EBV in latently infected cells by blocking tyrosine kinase phosphorylation [Miller 1995].…”

Virally targeted therapies for EBV-associated malignancies

“…In vivo, it is thus likely EBV tends to stay in the latent form of infection in quiescent B cells, and switches to the lytic form of infection in highly activated B cells. The latent EBV gene product, LMP-2, is thought to play an important role in helping to maintain viral latency in B cells by suppressing the signal transduction cascades which are normally induced by B-cell activation (Miller et al, 1995).…”

Protein Kinase C-Independent Activation of the Epstein-Barr Virus Lytic Cycle

“…To determine whether TPA inducibility was a general feature of EBV-transformed marmoset lymphoblastoid cell lines, we studied two additional marmoset cell lines: FF41, which, like B95-8, was transformed by EBV from a patient with infectious mononucleosis, and W91, which was transformed by EBV from a patient with Burkitt's lymphoma (20,38). FF41 spontaneously expressed the lytic cycle (Fig.…”

“…How are BRLF1 and BZLF1 repressed during latency? Repression may involve a pathway downstream of the EBV latency gene LMP2A, since EBV containing mutations or deletions in LMP2A enters the viral lytic cycle at a higher rate than the wild type (38). It is not known whether each activation stimulus has a distinct mode of action on the promoters of the immediate-early genes.…”