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

Cancer Center Karolinska, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
Cellular & Molecular Biology Letters (Impact Factor: 1.59). 06/2009; 14(2):222-47. DOI: 10.2478/s11658-008-0045-2
Source: PubMed


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-kappaB and STAT pathways, which can provide us with important insights into the roles of LMP2A in the EBV-associated latency state and various malignancies.

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    • "The N-terminal domain contains multiple signaling domains, including an immunoreceptor tyrosine-based activation motif (ITAM) recognized by the Lyn/Syk kinases to transduce BCR signaling, and a PY motif that interacts with the NEDD4 family of ubiquitin ligases (Ikeda et al., 2000; Portis et al., 2002; Ikeda et al., 2003). Other signaling pathways downstream of these domains include PI3k/akt, RhoA, and MAPK/ERK (Heussinger et al., 2004; Pang et al., 2009; Dawson et al., 2012). "
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    Virologica Sinica 04/2015; 30(2). DOI:10.1007/s12250-015-3592-5
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    • "The process of B lymphocyte transformation by EBV relies on the usurpation of cellular growth promoting and antiapoptotic signaling pathways by viral proteins. For example, LMP2A mimics and modulates the signaling pathway of B-cell antigen receptor (BCR) whereas the LMP1 oncoprotein mimics a constitutively active CD40 receptor [2], [3]. These signaling pathways involve a number of protein kinases, which are functionally modulated by the activity of latent EBV antigens. "
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    PLoS ONE 04/2014; 9(4):e95688. DOI:10.1371/journal.pone.0095688 · 3.23 Impact Factor
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    • "LMP2A is the only one membrane protein expressed in the reservoir of circulating, latently EBV-infected resting B-cells [16]. LMP2A contributes to malignant transformation by intervening with multiple signaling pathways, especially the cell cycle and apoptotic pathways, thus plays important role in viral latency and tumorigenesis [17,18]. The ability of LMP2A to influence the balance of survival factors in B lymphocytes could be functionally important in Burkitt lymphoma and LMP2A expression in EBV-infected B cells may lead to the induction and maintenance of an activated, proliferative state that could ultimately result in the development of Hodgkin lymphoma [19,20]. "
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