Figure 1.

Schematic representation of major NF-κB activation pathways. In the classical pathway, binding of TNFα to the receptor triggers the sequential recruitment of the adaptors TRADD, TRAF2 and RIP to the membrane. TRAF2 then recruits the IKK complex composed of IKKα, IKKβ and IKKγ (NEMO) through mediation of kinases like TAK1, MEKK1, MEKK3. Activation of the IKK complex leads to the phosphorylation and ubiquitination of IκBα at specific residues followed by its degradation via the proteasome pathway. The p105 subunit of NF-κB then undergoes GSK3β and Tpl2 mediated phosphorylation at S⁹⁰³ and S⁹⁰⁷ and subsequent degradation. The heterodimer p50–p65 is then released and migrates to the nucleus where it undergoes a series of posttranslational modifications including phosphorylation, acetylation and methylation and binds to specific κB sites and activates NF-κB target genes [49, 205, 206]. The alternative pathway is IKKγ independent and is triggered by binding of the CD40, RANK, LTβR, BAFF ligands to their receptor, leading to recruitment of TRAF proteins and the sequential activation of NIK and IKKα. Activation of IKKα then induces the processing of the inhibitory protein p100. p100 proteolysis releases p52 which then translocates to the nucleus and triggers transcription of NF-κB target genes [207]. NF-κB activation in response to UV-C does not depend on IKK activation and relies on sequential recruitment of p38MAPK and CKII. Activated CKII phosphorylates IκBα at C-terminus (S²⁸³-T²⁹⁹). The phosphorylated IκBα undergoes ubiquitination and degradation leading to release of active NF-κB in to the nucleus [208, 209]. EGF induced NF-κB activation proceeds without serine phosphorylation and ubiquitination of IκBα and is IKK independent. It relies on phosphorylation of IκBα at Tyr⁴² through mediation of tyrosine kinases that triggers its proteasome mediated degradation and subsequent release of active NF-κB to the nucleus [210]. NF-κB activation in response to bacterial endotoxin LPS involves Toll like receptor and is mediated through recruitment of MyD88, TRAF6 and ECSIT. Recruitment of these adaptors leads to sequential activation of IRAK1/2 and IKK and eventual release of active NF-κB [211]. NF-κB activation by pervanadate and H₂O₂ induces phosphorylation of IκBα at Tyr⁴² by protein tyrosine kinase like Syk. The Tyr phosphorylation does not lead to IκBα degradation but makes the binding weak thereby dissociating the IκBα and releasing active NF-κB to the nucleus [212, 213]. Antigen receptor viz., T-cell receptor and B-cell receptor mediated signaling to NF-κB activation depends on recruitment of a trimolecular protein complex CARMA1-BCL10-MALT1. In this pathway PKCθ (in T cells) and PKCβ (in B cells) alongwith other kinases act upstream to the trimolecular complex to promote IKKγ polyubiquitination and consequent IKK activation. Activation of IKK through this pathway involves mediation of TRAF2, TRAF6, TAK1 and TAB1 [214, 215]. A novel pathway of NF-κB activation originating from the nucleus is associated with DNA damage. Double-stranded DNA breaks in response to genotoxic agents initiate signals that trigger SUMOylation of nuclear-localized IKKγ, preventing its nuclear export. Concomitantly, these breaks activate ATM which phosphorylates SUMO-modified IKKγ, promoting the removal of SUMO and enhancing IKKγ ubiquitination. Ubiquitinated IKKγ then translocates to the cytoplasm, where it activates IKK in cooperation with ATM and the ELKS protein, leading to IκBα phosphorylation and degradation, p65 nuclear translocation and induction of NF-κB dependent target genes [216–219]. NF-κB can also be regulated by phosphatases. WIP1, a Ser/Thr phosphatase was recently shown to negatively regulate NF-κB activation by dephosphorylating p65 at Ser⁵³⁶ [80].

Abbreviations: AgR, antigen receptor; ATM, ataxia-telangiectasia mutant; BAFF, B-cell activating factor; BCL, B-cell lymphoma; BCR, B cell receptor; CARMA, CARD-containing MAGUK protein; CD40L, CD40 ligand; CK, casein kinase; DSBS, Double-stranded DNA breaks; ECSIT, evolutionary conserved signaling intermediates on Toll pathways; EGF, epidermal growth factor; EGFR, EGF receptor; ELKS, glutamate, leucine, lysine, serine-rich protein; GSK, glycogen synthase kinase; Hsp90, heat shock protein 90; IκB, inhibitor of NF-κB; IKK, IκB kinase; IRAK, IL-1R-associated kinase; LTβ, lymphotoxin β; LPS, lipopolysaccharide; MALT, mucosa-associated lymphoid tissue; MAPK, mitogen activated protein kinase; MAPK/Erk kinase kinase; MyD88, myeloid differentiation factor; NF-κB, nuclear factor-κB; NIK, NF-κB-inducing kinase; NEMO, NF-κB essential modulator; PDK, Phosphoinositide-dependent kinase; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; PLC, phospholipase C; RANKL, receptor activator of NF-κB ligand; RIP, receptor-interacting protein; Syk, Spleen tyrosine kinase; TAB, TAK1-binding protein; TAK, transforming growth factor-β-activated kinase; TCR, T cell receptor; TLR, Toll-like receptor; TNF, tumour necrosis factor; TNFR1, TNF receptor 1; Tpl2, tumour progression locus-2; TRADD, TNF-receptor-associated death domain protein; TRAF, TNF-receptor-associated factor.