The signaling of LMP2A directly prevents apoptosis by activating the Ras/PI3K/AKT pathway to increase the levels of Bcl family members . apoptosis, as determined by increases in Annexin-V staining, and cleavage of caspase-8, ?3 and PARP. Additional studies show that LMP2A-expressing B cell lines demonstrate a Lyn- and Syk-dependent increase in sensitivity to Fas-mediated apoptosis, due to an LMP2A-dependent enhancement in Fas expression. These findings demonstrate the ability for LMP2A to directly increase a pro-apoptotic molecule and have implications for EBV latency as well as the treatment of EBV-associated malignancies. Keywords: B cells, Epstein-Barr computer virus, Latency Membrane Protein 2A (LMP2A), B cell receptor (BCR), Lyn, Syk, Fas (CD95), apoptosis, and PARP Introduction Epstein-Barr computer virus (EBV) is a member of the herpesvirus family that infects over 90% of the worlds populace . For many individuals, EBV Dioscin (Collettiside III) contamination manifests without symptoms. However in adolescents, the acquisition of EBV can lead to infectious mononucleosis, which is a disease that results in lymphadenopathy, fever, pharyngitis, and severe fatigue . After initial lytic contamination, the computer virus alters its gene expression profile into a state in which all latency genes are expressed, including the six different EBV nuclear antigens (EBNAs), three Latency Membrane Proteins (LMP) ?1 and ?2A, ?2B , and EBV encoded small RNAs (EBERs) . Ultimately, the immune system controls EBV production and EBV transitions into a latent state in which a more limited quantity of latency genes are expressed . Most individuals will harbor latently-infected B cells for the rest of their life with little result. However, EBV can be a source of significant morbidity and mortality in people who become immunocompromised or garner genetic mutations that predispose them to tumor development [5, 6]. As mentioned above, EBV expresses few viral genes during latency in vivo [7-10]. However, one EBV transcript that is recognized in both normal latency and pathogenic says is usually Latent Membrane Protein 2A (LMP2A) [10-13]. LMP2A is usually a 12 transmembrane protein that contains an amino terminal tail that is constitutively phosphorylated . You will find multiple sites for phosphorylation within the cytoplasmic tail, including tyrosine 112 that activates Lyn tyrosine kinase, and an immunoreceptor tyrosine activation motif Dioscin (Collettiside III) (ITAM) that activates Syk. LMP2A functions as a B cell receptor (BCR) mimic [15, 16] and activates many of the same proteins induced by the BCR after activation with antigen. Both the BCR and LMP2A in the beginning activate Lyn tyrosine kinase, followed by Syk [17, 18]. Subsequent to the activation of Syk, LMP2A activates B cell Linker protein (BLNK) , the Ras/PI3K/AKT pathway , NF-kB [21, 22] and the MAPK/ERK pathway . The LMP2A-dependent activation of these pathways confers the many effects of LMP2A on B cell biology and lymphomagenesis. LMP2A signaling CD14 influences multiple functions of B cells, but most importantly promotes cell survival [15, 20, 24-26]. The signaling of LMP2A directly prevents apoptosis by activating the Ras/PI3K/AKT pathway to increase the levels of Bcl family members . Additionally, LMP2A-mediated activation of the PI3K/AKT pathway prevents TGF-1-induced apoptosis by decreasing the cleavage of PARP and subsequent DNA fragmentation . LMP2A also protects B cells from BCR-induced apoptosis, but makes them exquisitely more dependent on NF-kB to mediate this effect . Alternatively, LMP2A indirectly prevents apoptosis by increasing the production of the pro-survival cytokine, IL-10, in human B cell lines . Taken together, EBV uses LMP2A to hijack normal BCR Dioscin (Collettiside III) signaling to protect its host cell from apoptosis and is therefore proposed to ultimately aid in prolonging EBV latent contamination and promoting tumor development. As mentioned above, EBV is usually associated with the development of B cell tumors including Burkitts lymphoma, Hodgkins lymphoma and lymphoproliferative disorders in the immunocompromised [4, 5, 29]. Due to the anti-apoptotic abilities of LMP2A, multiple studies have resolved the possible mechanisms by which LMP2A contributes to tumor development. In a mouse model, LMP2A accelerates the development of Burkitts lymphoma by decreasing apoptosis  and increasing the percentage of proliferating cells [31, 32], resulting in the advanced onset of tumor development [30-32]. Additionally, in human cells, LMP2A directly promotes the survival of surface immunoglobulin-negative B cells , which are the precursors of Hodgkins Reed Sternberg cells in Hodgkins lymphoma . Thus, there is significant evidence that LMP2A contributes Dioscin (Collettiside III) to tumor development by protecting cells from apoptosis that are normally induced by overexpression of c-myc and/or the loss of surface immunoglobulin..