Role of the Immunoreceptor Tyrosine-Based Activation Motif of Latent Membrane Protein 2A (LMP2A) in Epstein-Barr Virus LMP2A- Induced Cell Transformation

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 nonhematopoietic cell lines was blocked in those cells expressing an immunoreceptor tyrosine-based acti-vation 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. Epstein-Barr virus (EBV), a ubiquitous human herpesvirus,is an important human tumor virus that is causally associ-ated with various lymphoid and epithelioid malignancies, in-cluding Hodgkin’s lymphoma, Burkitt’s lymphoma, nasopha-ryngeal carcinoma, and gastric carcinoma (1). Characteristic of the herpesvirus family, EBV can persist in the human host as a lifelong latent infection; however, the molecular mechanisms underlying EBV’s persistence and contribution to cancer remain poorly understood. Latent membrane protein 2A (LMP2A) is routinely detected in most EBV-related malignan-cies (1–4) and therefore may be an important risk factor in EBV-associated tumorigenesis. LMP2A, consisting of a long N-terminal tail, 12 membrane-spanning domains, and a short C-terminal tail, forms aggregate patches on the surfaces of latent-infected cells and can also localize in perinuclear regions (5). The N-terminal tail of LMP2A contains eight constitutively phosphorylated tyrosine residues and several proline-rich regions that are essential for interactions between LMP2A and other cellular proteins (2, 6). The intracellular N terminus of LMP2A contains multiple functional domains, including an immunoreceptor tyrosine-based activation motif (ITAM) homologous to that found in B-cell receptor (BCR) Ig and Ig signaling subunits (7–9)