The Epstein-Barr Virus-Encoded LMP2A and LMP2B Proteins Promote Epithelial Cell Spreading and Motility

Allen, Michael D.; Young, Lawrence S.; Dawson, Christopher W.

doi:10.1128/jvi.79.3.1789-1802.2005

Cited by 63 publications

(30 citation statements)

References 65 publications

(79 reference statements)

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“…A completely independent verification of our findings requires that we ask how well correlated with type III NPC are ISG sets compared with other well-defined gene sets. The Molecular Signature Database (MSigDB) contains f1,500 such gene sets 7 associated with specific signals, including several ISG sets. To objectively evaluate our findings with the ISGs, we tested our data against the MSigDB collection of gene sets.…”

Section: Resultsmentioning

confidence: 99%

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IFN-α–Stimulated Genes and Epstein-Barr Virus Gene Expression Distinguish WHO Type II and III Nasopharyngeal Carcinomas

et al. 2007

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Nonkeratinizing nasopharyngeal carcinoma (NPC) is 100% associated with Epstein-Barr Virus (EBV) and divided into two subtypes (WHO types II and III) based on histology. We tested whether these subtypes can be distinguished at the molecular genetic level using an algorithm that analyzes sets of related genes (gene set enrichment analysis). We found that a class of IFN-stimulated genes (ISG), frequently associated with the antiviral response, was significantly activated in type III versus type II NPC. Consistent with this, replication of the endogenous EBV was suppressed in type III. A strong association was also seen with a subset of ISGs previously identified in systemic lupus erythematosus, another disease in which 'normal' EBV biology is deregulated, suggesting that this pattern of ISG expression may be linked to the increased EBV activity in both diseases. In contrast, unsupervised hierarchical clustering of the complete expression profiles failed to distinguish the two subsets. These results suggest that type II and III NPC have not originated from obviously distinct epithelial precursors; rather, the histologic differences may be a consequence of a differential antiviral response, involving IFNs, to chronic EBV infection. [Cancer Res 2007;67(2):474-81]

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Section: Resultsmentioning

confidence: 99%

“…Nonkeratinizing NPCs can be subdivided based on expression of the viral oncogene latent membrane protein (LMP) 1, whereas all express LMP2A (6), which has prosurvival functions, at least in B cells, and may promote NPC metastasis (7)(8)(9). Despite these advances, the origins of NPC remain relatively unclear.…”

Section: Introductionmentioning

confidence: 99%

IFN-α–Stimulated Genes and Epstein-Barr Virus Gene Expression Distinguish WHO Type II and III Nasopharyngeal Carcinomas

et al. 2007

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“…In the three-dimensional collagen gel assay, LMP2A expression renders migratory ability, and promotes the mobility of EBV-infected NPC cell lines [20]. However, another study shows that the MEK inhibitor, UO126, is ineffective at blocking the spread and motility of LMP2A-and LMP2B-expressing epithelial cell lines on the extracellular matrix, suggesting that the MAPK pathway is not involved in the LMP2A-and LMP2B-mediated spread and motility of epithelial cells [120]. It is possible that different signaling pathways are employed by LMP2A in the metastasis of different cancer types, and further investigations are necessary to unravel the exact mechanisms of LMP2A influence on cell motility.…”

Section: Mapk Pathwaymentioning

confidence: 97%

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

Pang

Lin

Peh

2009

Cellular and Molecular Biology Letters

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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 EBVassociated latency state and various malignancies.

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“…Although both LMP2A and LMP2B have been shown to promote motility and cell spread in epithelial cells, little is known about the function of LMP2B in B cells (2,18,61,75). The sequence homology of LMP2B to LMP2A suggests that both proteins may localize to similar cellular compartments and may have some functions in common.…”

mentioning

confidence: 99%

Epstein-Barr Virus Latent Membrane Protein 2B (LMP2B) Modulates LMP2A Activity

Rovedo

Longnecker

2007

J Virol

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Latent membrane protein 2A (LMP2A) and LMP2B are viral proteins expressed during Epstein-Barr virus (EBV) latency in EBV-infected B cells both in cell culture and in vivo. LMP2A has important roles in modulating B-cell receptor (BCR) signal transduction by associating with the cellular tyrosine kinases Lyn and Syk via specific phosphotyrosine motifs found within the LMP2A N-terminal tail domain. LMP2A has been shown to alter normal BCR signal transduction in B cells by reducing levels of Lyn and by blocking tyrosine phosphorylation and calcium mobilization following BCR cross-linking. Although little is currently known about the function of LMP2B in B cells, the similarity in structure between LMP2A and LMP2B suggests that they may localize to the same cellular compartments. To investigate the function of LMP2B, B-cell lines expressing LMP2A, LMP2B, LMP2A/LMP2B, and the relevant vector controls were analyzed. As was previously shown, cells expressing LMP2A had a dramatic block in normal BCR signal transduction as measured by calcium mobilization and tyrosine phosphorylation. There was no effect on BCR signal transduction in cells expressing LMP2B. Interestingly, when LMP2B was expressed in conjunction with LMP2A, there was a restoration of normal BCR signal transduction upon BCR cross-linking. The expression of LMP2B did not alter the cellular localization of LMP2A but did bind to and prevent the phosphorylation of LMP2A. A restoration of Lyn levels, but not a change in LMP2A levels, was also observed in cells coexpressing LMP2B with LMP2A. From these results, we conclude that LMP2B modulates LMP2A activity.

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The Epstein-Barr Virus-Encoded LMP2A and LMP2B Proteins Promote Epithelial Cell Spreading and Motility

Cited by 63 publications

References 65 publications

IFN-α–Stimulated Genes and Epstein-Barr Virus Gene Expression Distinguish WHO Type II and III Nasopharyngeal Carcinomas

IFN-α–Stimulated Genes and Epstein-Barr Virus Gene Expression Distinguish WHO Type II and III Nasopharyngeal Carcinomas

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

Epstein-Barr Virus Latent Membrane Protein 2B (LMP2B) Modulates LMP2A Activity

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