Map Key
Generic Enzyme
Generic kinase
Protein kinase
Lipid kinase
Generic phosphatase
Protein phosphatase
Lipid phosphatase
Generic phospholipase
Generic protease
RAS - superfamily
G beta/gamma
Regulators (GDI, GAP, GEF)
Generic channel
Ligand-gated channel
Voltage-gated channel
Normal process
Pathological process
Positive effect
Negative effect
Unspecified effect
Technical link
Disrupts in disease
Emerges in disease
Enhances in disease
Weakens in disease
Organsim specific interaction

Generic binding protein
Receptor ligand
Cell membrane glycoprotein
Transcription factor
Inorganic ion
Predicted metabolite or user's structure
Generic receptor
Receptors with enzyme activity

Normal process
Pathological process
Covalent modifications
Transcription regulation
MicroRNA binding
Influence on expression
Unspecified interactions
Pharmacological effect
Toxic effect
Group relation
Complex subunit
Similarity reaction
A complex or a group
Organism specific object

Transcription NF-kB signaling pathway

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Transcription NF-kB signaling pathway

NF-kB signaling pathway

The Nuclear factor kappa B ( NF-kB ) plays a crucial role in immune andinflammatory responses through the regulation of genes encoding pro-inflammatorycytokines, adhesion molecules, chemokines, growth factors and inducible enzymes.Transcription factors of the NF-kB family are activated in response to signalsthat lead to cell growth, differentiation, apoptosis and other events. NF-kB isactivated by signals that activate Nuclear factor NF-kappa-B inhibitor kinase (IKK ) resulting in the phosphorylation of Nuclear factor of kappa lightpolypeptide gene enhancer in B-cells inhibitor ( I-kB ), this targets I-kBfor degradation in the proteasome and frees the NF-kB dimer, which thentranslocates to the nucleus and activates target genes [1].

Tumor necrosis factor ( TNF-alpha ) activates NF-kB via canonicalphosphorylation of IKK mediated by TNFRSF1A-associated via death domain (TRADD )/ TNF receptor-associated factor 2 ( TRAF2 )/ Mitogen-activatedprotein kinase kinase kinase 14 ( NIK(MAP3K14) ) [2]. Thenon-canonical pathway of NF-kB activation is utilized in response to the ligationof only certain TNF receptor superfamily members, for example Lymphotoxin betareceptor ( LTBR(TNFRSF3) ). In the non-canonical pathway, TRAF stimulatesNIK, which subsequently activates IKK-alpha by phosphorylation.IKK-alpha promotes the processing of nuclear factor of kappa light polypeptidegene enhancer in B-cells 2 ( NF-kB2 (p100) ) from p100 to p52 form. Furtherprocessed NF-kB2 is bound to V-rel reticuloendotheliosis viral oncogene homolog B( RelB ). NF-kB p52/RelB dimer is translocated into the nucleus to affectgene transcription. The non-canonical pathway is independent on IKK-beta andIKK-gamma [3], [1].

T cell receptor ( TCR ) and CD28 molecule ( CD28 ) can stimulateNF-KB via Protein kinase C theta ( PKC-theta )-dependent pathway [4], [5], [6]. Also CD28 triggers V-akt murinethymoma viral oncogene homolog 1 ( AKT )-mediated pathway [5].

Upon binding of Interleukin 1 ( IL-1 ), the Interleukin 1 receptor type I (IL-1RI ) associates with Interleukin 1 receptor accessory protein ( IL1RAP), forming a functional signaling receptor complex that recruits myeloid differentiationprimary response gene 88 ( MyD88 ). This leads to the translocation into thiscomplex of Interleukin-1 receptor-associated kinase ( IRAK1/2 ) together with Tollinteracting protein ( TOLLIP ). IRAK1 binds TNF receptor-associated factor6 ( TRAF6 ). After dissociation from the receptor complex, IRAK1/TRAF6 induces NIK or Mitogen-activated protein kinase kinase kinase 1 (MEKK1(MAP3K1) )-dependent phosphorylation of IKK [7].

Lipopolysacccharide ( LPS ) in complex with Lipopolysaccharide binding protein( LBP ) binds CD14 molecule ( CD14 ) on the cell membrane. It transfersLPS to lymphocyte antigen 96 ( MD- 2 ) and Toll-like receptor 4 (TLR4 ). TLR4 via binding MyD88 [7] and/or possiblyReceptor-interacting serine-threonine kinase 2 ( RIPK2 ) induces NF-kB-activating cascade [8].