Figure 3: Cell proliferation and cell survival pathways mediated by TNF-α. Retention of Complex 1 on the cell surface commits the cell to proliferate via two signal transduction pathways: nuclear factor κB (NF-κB) and mitogen activated protein kinase (MAPK). Polyubiquination of RIP1 releases NF-κB essential modulator (NEMO) or the γ subunit of IκB kinase (IKK) and recruits both transforming growth factor-β activated kinase-1 (TAK1) and inhibitor of κB kinase (IKK). Active TAK1 phosphorylates the IKK complex (IKK-α, -β, and -γ) which phosphorylates IκB. Phospho-IκB is ubiquinated, released from the transcription factor NF-κB, and targeted for degradation by the proteasome. NF-κB translocates to the nucleus to activated transcription. Binding of TNF-α to TNFR1 may also form another version of Complex 1 which consists of oligomers of TRAF2 bound to TNFR1, and TRAF2 recruits MAPK kinase kinase (MAPKKK) to the complex. MAPKKK phosphorylates MAPK kinase (MAPKK) which phosphorylates two terminal MAPKs, c-Jun N-terminal kinase (JNK) and extracellular signal-related kinase-1 and -2 (ERK 1/2). Phospho-JNK and phospho-ERK 1/2 translocate to the nucleus to activate transcription.