Home » Key Scientific Articles » Role of the immunoreceptor tyrosine-based activation motif of latent membrane protein 2A (LMP2A) in Epstein-Barr virus LMP2A-induced cell transformation

Role of the immunoreceptor tyrosine-based activation motif of latent membrane protein 2A (LMP2A) in Epstein-Barr virus LMP2A-induced cell transformation

Significance Statement 

Epstein-Barr virus (EBV), a ubiquitous human herpesvirus, is an important human tumor virus that is causally associated with various lymphoid and epithelioid malignancies, including Hodgkin’s lymphoma, Burkitt’s lymphoma, nasopharyngeal carcinoma, and gastric carcinoma. The underling mechanism of how EBV persists in humans and how the virus contributes to caner is still poorly understood. Latent membrane protein 2A (LMP2A) of EBV is widely expressed in EBV-infected cells in infected humans and in EBV-associated malignancies. We hypothesize that Latent membrane protein 2A may play not only a key role in ensuring EBV latency in healthy individuals but also may work as an enhancing tumorigenic factor in EBV associated diseases. We have shown that Latent membrane protein 2A -mediated cell survival effects and LMP2A-induced transformation ability in a human nonhematopoietic cell line. In addition, we propose that LMP2A’s effect on virus-induced tumorigenesis arises from a combination of relative effects of (i) host cell type and origin, (ii) host cellular transformation activity, and (iii) LMP2A-induced signaling pathways. In this study, to clarify the generality of the transforming ability of Latent membrane protein 2A in several human cell lines and to investigate the role of the Latent membrane protein 2A immunoreceptor tyrosine-based activation motif (ITAM) in LMP2A-induced cell transformation, we used several human cell lines, a human gastric carcinoma cell line HSC-39, a human breast cancer cell line, MCF-7 and human epithelial cell line transformed by DNA from adenovirus, 293, as an in vitro model for evaluating Latent membrane protein 2A -mediated transformation ability. As we have shown previously, Latent membrane protein 2A induced Akt phsophorylation and anchorage-independent cell growth in HSC-39 cells, MCF-7 cells and 293 cells; however, these effects were blocked in those cells expressing ITAM LMP2A mutant. In addition, the Syk inhibitor or Syk-specific small interfering RNA (siRNA) inhibited LMP2A-induced transformation.

These results indicate that the generality of the LMP2A-induced transformation activity in several human cell lines and the interaction of the Latent membrane protein 2A ITAM with Syk is a key step for LMP2A-mediated transformation. This study is the first report to clarify the direct relationship between the ITAM of LMP2A and LMP2A-mediated transformation activity. And further, as a mechanism of LMP2A mediated transformation, LMP2A manipulates host celluar protein kinase and induces cell transformation. Our findings will contribute to the understanding of the discipline and might contribute to the development of EBV therapy approaches in the future.

Epstein-Barr virus

 

 

 

 

 

 

 

Journal Reference

Fukuda M*, Kawaguchi Y.

J Virol. 2014 May;88(9):5189-94.

Division of Viral Infection, Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.

E-mail : [email protected]

 

Abstract

 Latent membrane protein 2A (LMP2A) of Epstein-Barr virus (EBV) is widely expressed in EBV-associated malignancies. We demonstrate that LMP2A has a transformation ability. This study shows that LMP2A-induced transformation in several human non hematopoietic cell line was blocked in those cells expressing an immunoreceptor tyrosine-based activation motif  (ITAM) LMP2A mutant. The Syk inhibitor or Syk-specific small interfering RNA (siRNA) inhibited LMP2A-induced transformation. These results indicate that the interaction of the LMP2A ITAM with Syk is a key step for LMP2A-mediated transformation.

Go To PubMed