Epstein-Barr Virus LMP2A Drives B Cell Development and Survival in the Absence of Normal B Cell Receptor Signals

Abstract

Epstein-Barr virus (EBV) establishes a persistent latent infection in peripheral B lymphocytes in humans and is associated with a variety of malignancies and proliferative disorders. Latent membrane protein 2A (LMP2A) is one of only two viral proteins expressed in latently infected B lymphocytes in vivo. LMP2A blocks B cell receptor (BCR) signal transduction in vitro by binding the Syk and Lyn protein tyrosine kinases. To analyze the significance of LMP2A expression in vivo, transgenic mice with B cell lineage expression of LMP2A were generated. LMP2A expression results in the bypass of normal B lymphocyte developmental checkpoints allowing immunoglobulin-negative cells to colonize peripheral lymphoid organs, indicating that LMP2A possesses a constitutive signaling activity in nontransformed cells.

Epstein-Barr virus–associated lymphoproliferative disorders

“…LMP1 and LMP2A may mimic and replace survival signals induced by activated CD40 and BCR, respectively. LMP1 resembles a constitutively active CD40 receptor [33], whereas LMP2A has been reported to mimic the presence of BCR in transgenic mice [34]. In addition to mimicking an activated CD40 receptor, LMP1 has also been postulated to prohibit apoptosis by upregulating the antiapoptotic protein bcl-2 [35] and mediating the activation of the nuclear factor-κB (NF-κB) signaling pathway [36].…”

The Shb signalling scaffold binds to and regulates constitutive signals from the Epstein–Barr virus LMP2A membrane protein

“…In B cells, it can deliver signals that permit survival of B-cell receptor (BCR)-negative cells in the peripheral circulation (Caldwell et al, 1998;Merchant et al, 2000). These signals were shown to depend on a constitutive activation of the PI3K (phosphoinositide 3-kinase)-Akt signalling pathway (Scholle et al, 2000, Swart et al, 2000 mediated by the LMP2A ITAM motif.…”

Cellular ITAM-containing proteins are oncoproteins in nonhematopoietic cells

“…However, since their identification, it has been noted that a number of oncogenic viruses encode transmembrane ITAMcontaining proteins. These proteins include EpsteinBarr virus (EBV) LMP2A, murine mammary tumor virus (MMTV) Env, and Kaposi's sarcoma-associated herpesvirus (KSHV) K1 (Caldwell et al, 1998;Lee et al, 1998a;Katz et al, 2005). Studies of signaling by LMP2A (Longnecker et al, 1991;Caldwell et al, 1998;Swart et al, 2000) and K1 (Lee et al, 1998a;Lagunoff et al, 1999) in B cells suggests that these ITAMs are capable of signaling in a manner similar to traditional cellular ITAMs.…”

“…These proteins include EpsteinBarr virus (EBV) LMP2A, murine mammary tumor virus (MMTV) Env, and Kaposi's sarcoma-associated herpesvirus (KSHV) K1 (Caldwell et al, 1998;Lee et al, 1998a;Katz et al, 2005). Studies of signaling by LMP2A (Longnecker et al, 1991;Caldwell et al, 1998;Swart et al, 2000) and K1 (Lee et al, 1998a;Lagunoff et al, 1999) in B cells suggests that these ITAMs are capable of signaling in a manner similar to traditional cellular ITAMs. Additionally, nonhematopoietic cells expressing K1 and LMP2A are susceptible to transformation and in vivo tumor development (Lee et al, 1998b;Scholle et al, 2000;Prakash et al, 2002).…”