Schematic diagram of EBV-mediated oncogenic signaling pathway activation in EBV-positive diffuse large B-cell lymphoma of the elderly. LMP1 has a 6-transmembrane domain with a long cytoplasmic C-terminal chain. It can self-aggregate to activate itself constitutively and provide a platform to interact with downstream molecules. LMP1 provides a proliferation signal via activating NF-κB, PI3K/Akt, MEK-ERK, and JNK–AP-1 MAPK pathways. It also gives signal for cell cycle progression by enhancing cyclin-dependent kinase 2 and phosphorylation of Rb protein and by inhibiting p16 and p27. LMP1 can also activate bcl-2 to provide an antiapoptotic signal. CTAR1 can directly interact with TRAF1, 2, 3, and 5 to activate NF-κB, PI3K/Akt, MEK-ERK, and JNK–AP-1 MAPK pathways. CTAR2 needs TRADD to interact with TRAF2 to activate NF-κB. Both canonical and noncanonical pathways of NF-κB are activated to give proliferation signal to the nucleus. There are 3 putative JAK3-binding motifs between CTAR1 and CTAR2. However, this finding was not reproduced by others.^26-36  AP-1, activator protein 1; ERK, extracellular signal-regulated kinases; JAK3, Janus kinase 3; JNK, Jun amino-terminal kinases; MEK, MAPK/ERK kinase; PI3K, phosphatidylinositol 3-kinase; TRADD, tumor necrosis factor receptor type 1–associated DEATH domain; TRAF, tumor necrosis factor receptor–associated factor.