IMGENEX provides the most extensive portfolio of antibodies, research tools and indepth expertise of applications for studying NF-kappaB signaling.
The NF-kappaB family of transcription factors plays a central and common role in the signaling pathways of stress-induced apoptosis, inflammation and immune signaling through innate and adaptive immune responses.
NF-kappaB Pathway Product Listing
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NF-kB (Nuclear Factor-KappaB) is a heterodimeric protein composed of different combinations of members of the Rel family of transcription factors. The Rel/NF-kB family of transcription factors are involved mainly in stress-induced, immune, and inflammatory responses. In addition, these molecules play important roles during the development of certain hemopoietic cells, keratinocytes, and lymphoid organ structures. More recently, NF-kB family members have been implicated in neoplastic progression and the formation of neuronal synapses. NF-kB is also an important regulator in cell fate decisions, such as programmed cell death and proliferation control, and is critical in tumorigenesis (Ref.1).
NF-kB is composed of homo- and heterodimers of five members of the Rel family including NF-kB1(p50), NF-kB2 (p52), RelA (p65), RelB, and c-Rel (Rel). Hetero and Homo-dimerization of NF-kB proteins which exhibit differential binding specificities includes p50/RelA, p50/c-Rel, p52/c-Rel, p65/c-Rel, RelA/RelA, p50/p50, p52/p52, RelB/p50 and RelB/p52. All the Rel proteins contain a conserved N-terminal region, called the RHD (Rel Homology Domain). The N-terminal part of the RHD contains the DNA-binding domain, whereas the dimerization domain is located in the C-terminal region of the RHD. Close to the C-terminal end of the RHD lies the NLS (Nuclear Localization Signal), which is essential for the transport of active NF-kB complexes into the nucleus. NF-kB1 and RelA were the first NF-kB proteins to be identified. Their N-terminal 300 AA revealed high similarity to the oncoprotein v-Rel, its cellular homologue c-Rel and the Drosophila protein Dorsal what resulted in the terms Rel proteins and RHD. The Rel/NF-kB proteins can be divided into two groups: Only RelA (p65), RelB and c-Rel (and Dorsal and Dif in Drosophila) contain potent TDs (Transactivation Domains) within sequences C-terminal to the RHD. The TDs consist of abundant serine, acidic and hydrophobic aminoacids that are essential for transactivation activity. In contrast, p50 and p52 do not possess TDs, and therefore cannot act as transcriptional activators by themselves. NF-kB1and NF-kB2 are produced as p105 and p100 precursors, respectively. The NF-kB1 p105 precursor appears to undergo constitutive processing by the cellular proteasome that removes the C-terminal I-kB-like portion to generate p50. NF-kB2 p100 precursor can be processed to remove the I-kB-like C-terminus, allowing the active p52 N-terminal half to function in transcriptional regulation. Homo- or heterodimers of p50 and p52 were even reported to repress KappaB site-dependent transcription, possibly by competing with other transcriptionally active dimers (e.g. p50/RelA) for DNA binding (Ref.2).
NF-kB dimers are sequestered in the cytosol of unstimulated cells via non-covalent interactions with a class of inhibitor proteins, called IkBs. To date seven IkBs have been identified: IkB-alpha, IkB-beta, IkB-gamma, IkB-epsilon, BCL3, p100 and p105. All known IkBs contain multiple copies of a 30-33 aa sequence, called ankyrin repeats which mediate the association between IkB and NF-kB dimers. The ankyrin repeats interact with a region in the RHD of the NF-kB proteins and by this mask their NLS and prevent nuclear translocation. Signals that induce NF-kB activity cause the phosphorylation of IkBs, their dissociation and subsequent degradation, thereby allowing activation of the NF-kB complex. Activated NF-kB complex translocates into the nucleus and binds DNA at kB-binding motifs such as 5-prime GGGRNNYYCC 3-prime or 5-prime HGGARNYYCC 3-prime (where H is A, C, or T; R is an A or G purine; and Y is a C or T pyrimidine) and induce gene expression. The degradation of IkB proteins that permits NF-KappaB molecules to move into the nucleus is also carried out by the proteasome but only after prior phosphorylation of IkB by the IKK (IkB Kinase Complex). The IKK is composed of three subunits: two, IKK-alpha (IKK1) and IKK-beta (IKK2), are bonafide kinases, while the third, IKK-gamma (NEMO), has no catalytic activity but plays a critical regulatory role. IKK-alpha is the predominant IkB kinase. Phosphorylated IkB is recognized by Beta-TrCP, a component of the SCF (skp-1/Cul/F box) ubiquitin ligase complex that mediates poly-ubiquitination of I-kB and its subsequent proteasomal degradation. In contrast, IKK-alpha mediates the phosphorylation-dependent processing of p100, resulting in the generation of p52 (Ref.3).
NF-kB can be activated by exposure of cells to LPS (Lipopolysaccharides) or inflammatory cytokines such as TNF (Tumour Necrosis Factor) or IL-1 (Interleukin-1), growth factors, lymphokines, oxidant-free radicals, inhaled particles, viral infection or expression of certain viral or bacterial gene products, UV irradiation, B or T-Cell activation, and by other physiological and non physiological stimuli. The most potent NF-kB activators are the proinflammatory cytokines IL-1 and TNF, which cause rapid phosphorylation of kBs at two sites within their N-terminal regulatory domain. TNF, which is the best-studied activator, binds to its receptor and recruits a protein called TRADD (TNF-Associated Receptor Death Domain). TRADD binds to the TRAF2 (TNF Receptor-Associated Factor-2) that recruits NIK (NF-kB-Inducible Kinase). Both IKK1 and IKK2 have canonical sequences that can be phosphorylated by the MAP (Mitogen Activated Protein) kinase NIK/MEKK1 and both kinases can independently phosphorylate IkB-alpha or IkB-beta. TRAF2 also interacts with A20, a zinc finger protein whose expression is induced by agents that activate NF-kB. A20 functions to block TRAF2-mediated NF-kB activation. A20 also inhibits TNF and IL-1 induced activation of NF-KappaB suggesting that it may act as a general inhibitor of NF-kB activation. CD40, another member of the TNF receptor family, can signal the induced processing of p100 to p52. The ligand for CD40, CD40L (CD154), is expressed on activated CD4-T cells, and when it engages CD40 in a T:B interaction, can induce B-Cell proliferation and differentiation. CD40 signaling induces p100 processing through NIK in the non-canonical pathway. LT-BetaR (Lymphotoxin–Beta Receptor), which is critically important for the development and organization of lymphoid tissue also gives way to two separate pathways, one that activates the canonical NF-KappaB pathway and depends upon IKK-beta and IKK-gamma/NEMO and another that induces p100 processing dependent on NIK and IKK-alpha (Ref.4).
The recognition of bacterial and viral products by Toll-like receptors on cells of the innate immune system also results in NF-kB induction, leading to the production of proinflammatory cytokines and the activation of Antigen Presenting Cell for T-Cell costimulation in the adaptive immune response. Viral infection leads to the increased expression and secretion of the cytokine interferon gamma (IFN-gamma) from host cells. IFN-gamma activates the double-stranded RNA (dsRNA)-dependent serine-threonine protein kinase R (PKR). dsRNA produced during viral replication induces PKR dimerization, autophosphorylation, and activation of the eIF-2alpha kinase activity. When eIF-2alpha is phosphorylated, cellular and viral protein translation cannot efficiently occur. Alternatively, bacterial products or cellular stress can also activate PKR by an endogenous gene product called PACT. The binding of PACT to PKR promotes conformational changes that allow PKR to activate the downstream signaling pathways leading to the activation of NF-KappaB.
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