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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Available from: Kah-Wai Lin, Oct 06, 2015
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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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    ABSTRACT: Nasopharyngeal carcinoma (NPC) is closely associated with Epstein-Barr virus (EBV) infection. EBV episomes are detected in almost all NPC cells. The role of EBV in NPC pathogenesis has long been postulated but remains enigmatic. In contrast to infection of B lymphocytes, EBV infection does not directly transform nasopharyngeal epithelial cells into proliferative clones with malignant potential. EBV infection of normal pharyngeal epithelial cells is predominantly lytic in nature. Genetic alterations in premalignant nasopharyngeal epithelium, in combination with inflammatory stimulation in the nasopharyngeal mucosa, presumably play essential roles in the establishment of a latent EBV infection in infected nasopharyngeal epithelial cells during the early development of NPC. Establishment of latent EBV infection in premalignant nasopharyngeal epithelial cells and expression of latent viral genes, including the BART transcripts and BART-encoded microRNAs, are crucial features of NPC. Expression of EBV genes may drive further malignant transformation of premalignant nasopharyngeal epithelial cells into cancer cells. The difficulties involved in the establishment of NPC cell lines and the progressive loss of EBV epsiomes in NPC cells propagated in culture strongly implicate the contribution of host stromal components to the growth of NPC cells in vivo and maintenance of EBV in infected NPC cells. Defining the growth advantages of EBV-infected NPC cells in vivo will lead to a better understanding of the contribution of EBV infection in NPC pathogenesis, and may lead to the identification of novel therapeutic targets for NPC treatment.
    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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    ABSTRACT: Epstein-Barr virus (EBV) is a human herpesvirus, which is causally associated with the development of several B lymphocytic malignancies that include Burkitt's lymphomas, Hodgkin's disease, AIDS and posttransplant associated lymphomas. The transforming activity of EBV is orchestrated by several latent viral proteins that mimic and modulate cellular growth promoting and antiapoptotic signaling pathways, which involve among others the activity of protein kinases. In an effort to identify small molecule inhibitors of the growth of EBV-transformed B lymphocytes a library of 254 kinase inhibitors was screened. This effort identified two tyrosine kinase inhibitors and two MEK inhibitors that compromised preferentially the viability of EBV-infected human B lymphocytes. Our findings highlight the possible dependence of EBV-infected B lymphocytes on specific kinase-regulated pathways underlining the potential for the development of small molecule-based therapeutics that could target selectively EBV-associated human B lymphocyte malignancies.
    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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    ABSTRACT: Latent membrane protein (LMP) 1 and LMP2A encoded by Epstein-Barr virus (EBV) are associated with the development of malignancies, but their expression in extranodal NK/T-cell lymphoma, nasal type (ENKTL) and the relationship with clinical characteristics of this disease remain poorly understood. In the present study, we examined the expression of LMP1 and LMP2A in ENKTL, and investigated the correlations between LMP1 and LMP2A expression with clinicopathological characteristics of ENKTL patients. Paraffin sections of surgically removed samples from 16 ENKTL patients were analyzed by immunohistochemistry and the related clinicopathological data were collected and analyzed. Elevated expression (immunohistochemistry score ≥ 4) of LMP1 and LMP2A was detected in the tumor cells of ENKTL. High LMP1 expression was associated with positive B symptoms (p = 0.012), while high LMP2A expression was related to gender (p = 0.029). The expression of both LMP1 and LMP2A showed significant correlations with patients’ overall survival (p = 0.049, p = 0.036). LMP1 and LMP2A may be prognostic indicators of survival in patients with ENKTL. Virtual slides
    Diagnostic Pathology 12/2012; 7(1):178. DOI:10.1186/1746-1596-7-178 · 2.60 Impact Factor
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