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The signaling pathways of Epstein-Barr virus-encoded latent membrane protein 2A (LMP2A) in latency and cancer

Abstract

Epstein-Barr virus (EBV) is a ubiquitous virus with infections commonly resulting in a latency carrier state. Although the exact role of EBV in cancer pathogenesis remains not entirely clear, it is highly probable that it causes several lymphoid and epithelial malignancies, such as Hodgkin’s lymphoma, NK-T cell lymphoma, Burkitt’s lymphoma, and nasopharyngeal carcinoma. EBV-associated malignancies are associated with a latent form of infection, and several of these EBV-encoded latent proteins are known to mediate cellular transformation. These include six nuclear antigens and three latent membrane proteins. Studies have shown that EBV displays distinct patterns of viral latent gene expression in these lymphoid and epithelial tumors. The constant expression of latent membrane protein 2A (LMP2A) at the RNA level in both primary and metastatic tumors suggests that this protein might be a driving factor in the tumorigenesis of EBV-associated malignancies. LMP2A may cooperate with the aberrant host genome, and thereby contribute to malignant transformation by intervening in signaling pathways at multiple points, especially in the cell cycle and apoptotic pathway. This review summarizes the role of EBV-encoded LMP2A in EBV-associated viral latency and cancers. We will focus our discussions on the molecular interactions of each of the conserved motifs in LMP2A, and their involvement in various signaling pathways, namely the B-cell receptor blockade mechanism, the ubiquitin-mediated (Notch and Wnt) pathways, and the MAPK, PI3-K/Akt, NK-κB and STAT pathways, which can provide us with important insights into the roles of LMP2A in the EBV-associated latency state and various malignancies.

Abbreviations

BCR:

B-cell receptor

BL:

Burkitt’s lymphoma

EBER:

EBV-encoded small non-polyadenylated RNA

EBNA:

EBV nuclear antigen

EBV:

Epstein-Barr virus

ERK:

extracellular signal-regulated kinase

GSK-3β:

glycogen synthase kinase-3 beta

HL:

Hodgkin’s lymphomas

IkBα:

inhibitor of NF-κB alpha

IL:

interleukin

ITAM:

immunoreceptor tyrosine-based activation motif

JNK:

c-Jun-N-terminal kinase

LMP:

latent membrane protein

MAPK:

mitogen-activated protein kinase

NHL:

non-Hodgkin’s lymphomas

NK-κB:

nuclear factor-kappa B

NPC:

nasopharyngeal carcinoma

PI3-K:

phosphotidylinositol 3-kinase

PTK:

protein tyrosine kinase

STAT:

signal transducers and activators of transcription

TGF-β:

transforming growth factor-beta

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Correspondence to Suat-Cheng Peh.

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Pang, MF., Lin, KW. & Peh, SC. The signaling pathways of Epstein-Barr virus-encoded latent membrane protein 2A (LMP2A) in latency and cancer. Cell Mol Biol Lett 14, 222–247 (2009). https://doi.org/10.2478/s11658-008-0045-2

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  • DOI: https://doi.org/10.2478/s11658-008-0045-2

Key words

  • Epstein-Barr virus
  • Latent membrane protein
  • Cancer
  • Latency