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

2009 ◽  
Vol 14 (2) ◽  
Author(s):  
Mei-Fong Pang ◽  
Kah-Wai Lin ◽  
Suat-Cheng Peh
Keyword(s):  
Membrane Protein ◽  
Signaling Pathways ◽  
Epstein Barr Virus ◽  
Cellular Transformation ◽  
Latent Membrane Protein ◽  
Latent Membrane Protein 2A ◽  
Barr Virus ◽  
Cancer Pathogenesis ◽  
Epstein Barr

AbstractEpstein-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.

scholarly journals Role of Epstein–Barr virus-encoded latent membrane protein 2A on virus-induced immortalization and virus activation

2001 ◽  
Vol 82 (6) ◽  
pp. 1451-1456 ◽  
Author(s):  
Kazuya Konishi ◽  
Seiji Maruo ◽  
Hiroyuki Kato ◽  
Kenzo Takada
Keyword(s):  
Membrane Protein ◽  
B Lymphocytes ◽  
Virus Replication ◽  
Epstein Barr Virus ◽  
Latent Membrane Protein ◽  
Latent Membrane Protein 2A ◽  
Barr Virus ◽  
Epstein Barr

To quantitatively evaluate the role of Epstein-Barr virus (EBV)-encoded latent membrane protein 2A (LMP2A) in immortalization of peripheral B-lymphocytes, we used the Akata cell system to generate an EBV recombinant in which the first exon of the LMP2A gene was disrupted. The results indicated that deletion of the LMP2A gene did not affect the immortalization efficiency of EBV in B-lymphocytes. Deletion of the LMP2A gene made EBV-transformed lymphocytes more permissive for virus replication in response to surface immunoglobulin cross-linking. On the other hand Akata cells, in which LMP2A expression was much lower than in EBV-transformed lymphocytes, were equally permissive for virus replication whether they were infected with wild EBV or LMP2A-knockout EBV. The results raise a question as to the role of LMP2A in inhibition of disruption of virus latency in vivo, where LMP2A expression has been expected to be low as in Akata cells.

scholarly journals Epstein-Barr Virus Latent Membrane Protein 2a (Lmp2a) Employs the Slp-65 Signaling Module

2001 ◽  
Vol 194 (3) ◽  
pp. 255-264 ◽  
Author(s):  
Niklas Engels ◽  
Mark Merchant ◽  
Rajita Pappu ◽  
Andrew C. Chan ◽  
Richard Longnecker ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Signaling Pathways ◽  
Epstein Barr Virus ◽  
Antigen Receptor ◽  
Adaptor Protein ◽  
Latent Membrane Protein ◽  
Latent Membrane Protein 2A ◽  
Barr Virus ◽  
Ebv Infection ◽  
Epstein Barr

In latently infected B lymphocytes, the Epstein-Barr virus (EBV) suppresses signal transduction from the antigen receptor through expression of the integral latent membrane protein 2A (LMP2A). At the same time, LMP2A triggers B cell survival by a yet uncharacterized maintenance signal that is normally provided by the antigen receptor. The molecular mechanisms are unknown as LMP2A-regulated signaling cascades have not been described so far. Using a novel mouse model we have identified the intracellular adaptor protein Src homology 2 (SH2) domain–containing leukocyte protein (SLP)-65 as a critical downstream effector of LMP2A in vivo. Biochemical analysis of the underlying signaling pathways revealed that EBV infection causes constitutive tyrosine phosphorylation of one of the two SLP-65 isoforms and complex formation between SLP-65 and the protooncoprotein CrkL (CT10 regulator of kinase like). This leads to antigen receptor-independent phosphorylation of Cbl (Casitas B lineage lymphoma) and C3G. In contrast, phospholipase C-γ2 (PLC-γ2) activation is completely blocked. Our data show that in order to establish a latent EBV infection, LMP2A selectively activates or represses SLP-65–regulated signaling pathways.

Role of latent membrane protein 2 isoforms in Epstein–Barr virus latency

2008 ◽  
Vol 16 (11) ◽  
pp. 520-527 ◽  
Author(s):  
Markus P. Rechsteiner ◽  
Michele Bernasconi ◽  
Christoph Berger ◽  
David Nadal
Keyword(s):  
Membrane Protein ◽  
Epstein Barr Virus ◽  
Latent Membrane Protein ◽  
Barr Virus ◽  
Virus Latency ◽  
Epstein Barr ◽  
Latent Membrane Protein 2

scholarly journals Elucidation of the c-Jun N-Terminal Kinase Pathway Mediated by Epstein-Barr Virus-Encoded Latent Membrane Protein 1

2004 ◽  
Vol 24 (1) ◽  
pp. 192-199 ◽  
Author(s):  
Jun Wan ◽  
Luguo Sun ◽  
Jennifer Woo Mendoza ◽  
Yiu Loon Chui ◽  
Dolly P. Huang ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Epstein Barr Virus ◽  
Cellular Transformation ◽  
Latent Membrane Protein ◽  
Host Cells ◽  
Latent Membrane Protein 1 ◽  
Tnf Receptor ◽  
Jnk Pathway ◽  
Barr Virus ◽  
Epstein Barr

ABSTRACT Epstein-Barr virus (EBV) is associated with several human diseases including infectious mononucleosis and nasopharyngeal carcinoma. EBV-encoded latent membrane protein 1 (LMP1) is oncogenic and indispensable for cellular transformation caused by EBV. Expression of LMP1 in host cells constitutively activates both the c-Jun N-terminal kinase (JNK) and NF-κB pathways, which contributes to the oncogenic effect of LMP1. However, the underlying signaling mechanisms are not very well understood. Based mainly on overexpression studies with various dominant-negative constructs, LMP1 was generally thought to functionally mimic members of the tumor necrosis factor (TNF) receptor superfamily in signaling. In contrast to the prevailing paradigm, using embryonic fibroblasts from different knockout mice and the small interfering RNA technique, we find that the LMP1-mediated JNK pathway is distinct from those mediated by either TNF-α or interleukin-1. Moreover, we have further elucidated the LMP1-mediated JNK pathway by demonstrating that LMP1 selectively utilizes TNF receptor-associated factor 6, TAK1/TAB1, and c-Jun N-terminal kinase kinases 1 and 2 to activate JNK.

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