Unique signaling properties of CTAR1 in LMP1-Mediated transformation

The Epstein-Barr virus (EBV) latent membrane protein 1 (LMP1) gene is considered the EBV oncogene as it is necessary for EBV-mediated transformation of B lymphocytes and itself transforms rodent fibroblasts. LMP1 activates the NF-kappa B, phosphatidylinositol 3-kinase (PI2K)-Akt, mitogen- activated protein kinase, and Jun N-terminal protein kinase signaling pathways through its two signaling domains, carboxyl-terminal activating regions 1 and 2 (CTAR1 and CTAR2). CTARI and CTAR2 induce signal transduction pathways through their direct (CTARI) or indirect (CTAR2) recruitment of tumor necrosis factor receptor-associated factors (TRAFs). CTARI is necessary for LMP1-mediated transformation as well as activation of PI3K signaling and induction of cell cycle markers associated with G,(I)/S transition. In this study, activation of PI3K-Akt signaling and deregulation of cell cycle markers were mapped to the TRAF-binding domain within CTARI and to the residues between CTAR1 and CTAR2. LMP1 CTARI also activated the MEK1/2-extracellular signal -regulated kinase 1/2 signaling pathway, and this activation was necessary for LMP1-induced transformation of Rat-1 fibroblasts. Dominant-negative forms of TRAF2 and TRAF3 inhibited but did not fully block LMP1-mediated transformation. These findings identify a new signaling pathway that is uniquely activated by the TRAF-binding domain of LMP1 and is required for transformation.