Alternative pathway of NF-κB activation. In unstimulated cells, NIK is destabilized by bound TRAF3. Activation through a subset of receptors of the TNFR superfamily including the BAFFR, CD40, RANK and lymphotoxin-β R leads to the recruitment of TRAF proteins (including TRAF3) to the receptor. TRAF3 is inactivated (possibly by degradation or sequestration) and active NIK is thus released. NIK then phosphorylates and activates IKK; it also recruits NF-κB2/p100 (probably bound to RelB), which is phosphorylated by IKKα. This triggers K48 polyubiquitination of p100 mediated by β TrCP E3 ubiquitin ligase and subsequent proteasomal processing to yield the mature subunit p52. Predominantly RelB/p52 heterodimers are generated, which migrate to the nucleus. The classical pathway is also activated through these receptors with some receptors (BAFFR) activating less strongly than others. Unlike TNFR (Figure 2), BAFFR signaling is associated only with survival functions. BAFFR, B-cell activating factor receptor; IKK, IκB kinase; LT, lymphotoxin; NF-κB, nuclear factor-κB; NIK, NF-κB-inducing kinase; RANK, receptor activator of NF-κB; TNFR, tumor necrosis factor receptor; TRAF, TNF receptor-associated factor.