Classical pathway of NF-κB activation via IκB degradation. Ligand engagement of specific membrane receptors triggers K63 polyubiquitination of TRAF2, TRAF6, RIP, MALT1, and NEMO. The TAK kinase complex is recruited through association of the polyubiquitin chains with TAB2 and TAB3. Activated TAK1 may phosphorylate and activate IKKβ, which then phosphorylates IκB bound to cytosolic NF-κB, triggering its β TrCP E3 ubiquitin ligase-mediated K48 polyubiquitination and proteasomal degradation. Free NF-κB then translocates to the nucleus and transactivates target genes. CYLD and A20 are deubiquitinating enzymes that may block NF-κB activation by removal of K63 ubiquitinated chains from activated TRAFs, RIP, and NEMO. A20 may also terminate TNF-α induced NF-κB activation by catalyzing the K48 ubiquitination of RIP, leading to its proteasomal degradation. In addition to promoting survival via NF-κB target genes, the TNF receptor (TNFR1) also stimulates competing apoptotic pathways. T cell (and B cell) antigen receptors (TCR and BCR, respectively [not shown]) may in some contexts enhance apoptotic pathways but usually they contribute to survival (see text). IκB, inhibitor of NF-κB; IKK, IκB kinase; MALT, mucosa-associated lymphoid tissue lymphoma translocation gene; NEMO, NF-κB essential modulator; NF-κB, nuclear factor-κB; RIP, receptor interacting protein; TAB, TAK1-binding protein; TAK, transforming growth factor β-activated kinase; TRAF, TNF receptor-associated factor.