_enti_e7
_enti_e8
_enti_e9
_enti_e1
_enti_e10
_enti_e2
_enti_e4
_enti_e3
_enti_e55
_enti_e53
_enti_e59
_enti_e54
_enti_e52
_enti_e51
_enti_e56
_enti_e50
_enti_e58
_enti_e61
_enti_e57
_enti_e62
_enti_e60
g1_fact_g1
g2_fact_g12
g2_fact_g13
g1_fact_g14
p1_propro_p1
PMID: 18267068
IκBα is rapidly degraded during activation of canonical NF-κB signaling pathways leading to the release of multiple NF-κB dimers, although the p65:p50 heterodimer is likely the primary target of IκBα.
PMID: 18267068, 9660950
PKA exists in a complex with cytosolic NF-κB:IκB complexes and following degradation of IκBα phosphorylates p65 at Ser276, promoting the interaction of p65 with the transcriptional coactivators CBP (CREB-binding protein) and p300
c1 cso30:c:InputProcess connector
c3 cso30:c:InputProcess connector
c269 cso30:c:InputProcess connector
c270 cso30:c:OutputProcess connector
p2_propro_p2
PMID: 18267068, 11983155
The exposed NLS of p50 coupled with nuclear export sequences (NES) in IκBα and p65 leads to constant shuttling of IκBα/NF-κB complexes between the nucleus and the cytoplasm, despite steady-state localization that appears almost exclusively cytosolic
c4 cso30:c:InputProcess connector
c5 cso30:c:OutputProcess connector
p3_propro_p3
PMID: 18267068, 11983155
The exposed NLS of p50 coupled with nuclear export sequences (NES) in IκBα and p65 leads to constant shuttling of IκBα/NF-κB complexes between the nucleus and the cytoplasm, despite steady-state localization that appears almost exclusively cytosolic
c6 cso30:c:InputProcess connector
c7 cso30:c:OutputProcess connector
p5_propro_p5
PMID: 18267068
Constitutive binding of p50 or p52 homodimers to κB sites on NF-κB-responsive promoters may thus act to check NF-κB transactivation until displaced by transcriptionally competent NF-κB dimers.
c10 cso30:c:InputProcess connector
c11 cso30:c:OutputProcess connector
p6_propro_p6
PMID: 18267068
Constitutive binding of p50 or p52 homodimers to κB sites on NF-κB-responsive promoters may thus act to check NF-κB transactivation until displaced by transcriptionally competent NF-κB dimers.
c12 cso30:c:InputProcess connector
c13 cso30:c:InputProcess connector
c14 cso30:c:OutputProcess connector
p8_propro_p8
PMID: 18267068, 16732290
Likewise it has been shown that in T cells p100 also limits p65-mediated NF-κB activity in a negative feedback loop set up following T cell activation
c15 cso30:c:InputInhibitor connector
p9_propro_p9
PMID: 18267068
Degradation of IκB is a rapidly induced signaling event that is initiated upon specific phosphorylation of these molecules by activated IKK.
c153 cso30:c:InputAssociation connector
c271 cso30:c:InputProcess connector
c2 cso30:c:OutputProcess connector
p10_propro_p10
PMID: 18267068
The noncanonical pathway, conversely, depends only on the IKKα subunit, which functions by phosphorylating p100 and causing its inducible processing to p52.
c23 cso30:c:InputProcess connector
c91 cso30:c:InputAssociation connector
c24 cso30:c:OutputProcess connector
p11_propro_p11
PMID: 18267068, 17072324
Phosphorylation of the conserved serine residues (DS*GXXS*) in IκB proteins results in their K48-linked polyubiquitination by βTrCP containing Skp1-Culin-Roc1/Rbx1/Hrt-1-F-box (SCF) E3 ubiquitin ligase complexes (SCFβTrCP) coordinately with the E2 UbcH5.
c27 cso30:c:InputAssociation connector
c28 cso30:c:InputAssociation connector
c195 cso30:c:InputProcess connector
c25 cso30:c:OutputProcess connector
p12_propro_p12
PMID: 18267068, 17072324
Phosphorylation of the conserved serine residues (DS*GXXS*) in IκB proteins results in their K48-linked polyubiquitination by βTrCP containing Skp1-Culin-Roc1/Rbx1/Hrt-1-F-box (SCF) E3 ubiquitin ligase complexes (SCFβTrCP) coordinately with the E2 UbcH5.
c26 cso30:c:InputProcess connector
c30 cso30:c:OutputProcess connector
c29 cso30:c:OutputProcess connector
p13_propro_p13
PMID: 18267068, 17072323
The released NF-κB dimers bind promoter and enhancer regions containing κB consensus sequences 5′ GGGRNWYYCC 3′ (Nany base; Rpurine; Wadenine or thymine; and Ypyrimidine)
c196 cso30:c:InputProcess connector
c33 cso30:c:OutputProcess connector
c272 cso30:c:OutputProcess connector
p14_propro_p14
c35 cso30:c:InputAssociation connector
c34 cso30:c:OutputProcess connector
p15_propro_p15
PMID: 18267068, 17072323
The released NF-κB dimers bind promoter and enhancer regions containing κB consensus sequences 5′ GGGRNWYYCC 3′ (Nany base; Rpurine; Wadenine or thymine; and Ypyrimidine)
c36 cso30:c:InputProcess connector
c279 cso30:c:InputProcess connector
c38 cso30:c:OutputProcess connector
p16_propro_p16
PMID: 18267068
Thus when IL-1R binds IL-1 or RIG-I binds cytoplasmic dsRNA they activate overlapping but unique signaling pathways due to these differences in upstream signaling components, and hence they induce distinct transcriptional programs.
c39 cso30:c:InputProcess connector
c40 cso30:c:InputProcess connector
c41 cso30:c:OutputProcess connector
p17_propro_p17
PMID: 18267068, 17047224
For example, IL-1R and RIG-I, which both signal through TRAF6 to IKK, do so through distinct receptor proximal adaptor components MyD88 and MAVS, respectively
c42 cso30:c:InputProcess connector
c43 cso30:c:InputProcess connector
c44 cso30:c:OutputProcess connector
p20_propro_p20
PMID: 18267068, 8565075
Following binding of TNFα, TRAF2 is recruited to TNFR1 through its interaction with TRADD
c57 cso30:c:InputProcess connector
c59 cso30:c:InputProcess connector
c58 cso30:c:OutputProcess connector
p21_propro_p21
PMID: 18267068
It is important to bear in mind that although diverse upstream events may mediate IKK activation through a common mechanism, parallel signaling pathways emanating from nonredundant receptor proximal signaling components frequently produce crosstalk that shapes the NF-κB response in ways that are unique to individual signaling pathways.
PMID: 18267068
The core elements of NF-κB signaling pathways are generally several steps removed from the receptor itself. The intervening steps between receptor and IKK form links to parallel signaling pathways.
c53 cso30:c:InputAssociation connector
c146 cso30:c:InputProcess connector
c52 cso30:c:OutputProcess connector
p22_propro_p22
PMID: 18267068
It is important to bear in mind that although diverse upstream events may mediate IKK activation through a common mechanism, parallel signaling pathways emanating from nonredundant receptor proximal signaling components frequently produce crosstalk that shapes the NF-κB response in ways that are unique to individual signaling pathways.
PMID: 18267068
The core elements of NF-κB signaling pathways are generally several steps removed from the receptor itself. The intervening steps between receptor and IKK form links to parallel signaling pathways.
c56 cso30:c:InputAssociation connector
c54 cso30:c:InputProcess connector
c21 cso30:c:OutputProcess connector
p23_propro_p23
PMID: 18267068, 8565075
Following binding of TNFα, TRAF2 is recruited to TNFR1 through its interaction with TRADD
c60 cso30:c:InputProcess connector
c61 cso30:c:InputProcess connector
c62 cso30:c:OutputProcess connector
p24_propro_p24
PMID: 18267068, 8565075
Following binding of TNFα, TRAF2 is recruited to TNFR1 through its interaction with TRADD
c63 cso30:c:InputProcess connector
c64 cso30:c:InputProcess connector
c65 cso30:c:OutputProcess connector
p25_propro_p25
PMID: 18267068
TRAF5 was also shown to interact with the TNFR1 signaling complex,
c66 cso30:c:InputProcess connector
c67 cso30:c:InputProcess connector
c68 cso30:c:OutputProcess connector
p27_propro_p27
PMID: 18267068
TRAF2 and TRAF5 are together required for NF-κB activation by TNFR1.
c69 cso30:c:InputAssociation connector
c71 cso30:c:InputProcess connector
c72 cso30:c:OutputProcess connector
p26_propro_p26
c74 cso30:c:InputAssociation connector
c70 cso30:c:InputProcess connector
c73 cso30:c:OutputProcess connector
p28_propro_p28
PMID: 18267068, 17047224, 17072327
In Toll/IL-1 signaling TRAF6 is recruited to the receptor complex and is necessary for MyD88-dependent activation of NF-κB by IL-1 and ligands of TLR4
c75 cso30:c:InputProcess connector
c77 cso30:c:InputProcess connector
c76 cso30:c:OutputProcess connector
p29_propro_p29
PMID: 18267068, 17047224, 17072327
In Toll/IL-1 signaling TRAF6 is recruited to the receptor complex and is necessary for MyD88-dependent activation of NF-κB by IL-1 and ligands of TLR4
c78 cso30:c:InputProcess connector
c79 cso30:c:InputProcess connector
c80 cso30:c:OutputProcess connector
p30_propro_p30
PMID: 18267068, 17047224, 17072327
In Toll/IL-1 signaling TRAF6 is recruited to the receptor complex and is necessary for MyD88-dependent activation of NF-κB by IL-1 and ligands of TLR4
c81 cso30:c:InputProcess connector
c82 cso30:c:InputProcess connector
c83 cso30:c:OutputProcess connector
p31_propro_p31
PMID: 18267068, 17047224, 17072327
In Toll/IL-1 signaling TRAF6 is recruited to the receptor complex and is necessary for MyD88-dependent activation of NF-κB by IL-1 and ligands of TLR4
c84 cso30:c:InputProcess connector
c85 cso30:c:InputProcess connector
c86 cso30:c:OutputProcess connector
p32_propro_p32
PMID: 18267068, 15708970
TRAF3, which interacts with receptors that trigger the alternative pathway, also interacts with NIK and it now appears that theactivation of NIK is negatively regulated by TRAF3.
c87 cso30:c:InputProcess connector
c88 cso30:c:InputProcess connector
c89 cso30:c:OutputProcess connector
p34_propro_p34
PMID: 18267068, 15708970
TRAF3, which interacts with receptors that trigger the alternative pathway, also interacts with NIK and it now appears that the activation of NIK is negatively regulated by TRAF3.
c92 cso30:c:InputProcess connector
c93 cso30:c:InputProcess connector
c94 cso30:c:OutputProcess connector
p35_propro_p35
PMID: 18267068, 15084608
In the resting state, TRAF3 induces NIK ubiquitination and degradation, but upon stimulation TRAF3 undergoes signal-dependent degradation, mediated by other TRAF family members, resulting in the accumulation and activation of NIK and consequent activation of the noncanonical pathway
c96 cso30:c:InputProcess connector
c98 cso30:c:InputAssociation connector
c97 cso30:c:OutputProcess connector
p36_propro_p36
PMID: 18267068, 15084608
In the resting state, TRAF3 induces NIK ubiquitination and degradation, but upon stimulation TRAF3 undergoes signal-dependent degradation, mediated by other TRAF family members, resulting in the accumulation and activation of NIK and consequent activation of the noncanonical pathway
c99 cso30:c:InputProcess connector
c100 cso30:c:OutputProcess connector
p37_propro_p37
PMID: 18267068, 15084608
In the resting state, TRAF3 induces NIK ubiquitination and degradation, but upon stimulation TRAF3 undergoes signal-dependent degradation, mediated by other TRAF family members, resulting in the accumulation and activation of NIK and consequent activation of the noncanonical pathway
c101 cso30:c:InputProcess connector
c102 cso30:c:OutputProcess connector
p38_propro_p38
PMID: 18267068, 15084608
In the resting state, TRAF3 induces NIK ubiquitination and degradation, but upon stimulation TRAF3 undergoes signal-dependent degradation, mediated by other TRAF family members, resulting in the accumulation and activation of NIK and consequent activation of the noncanonical pathway
c103 cso30:c:InputProcess connector
c104 cso30:c:OutputProcess connector
c105 cso30:c:OutputProcess connector
c106 cso30:c:OutputProcess connector
p39_propro_p39
PMID: 18267068
RIP family members have been implicated in most TRAF-dependent pathways, e.g., signaling from TNFR superfamily and Toll/IL-1R.
PMID: 18267068
RIP1 binds to NEMO and is essential for TNFα-induced IKK and NF-κB activation
c109 cso30:c:InputProcess connector
c107 cso30:c:InputProcess connector
c108 cso30:c:OutputProcess connector
p40_propro_p40
PMID: 18267068, 8565075, 9529147, 8947041, 10755617
RIP1 binds to NEMO and is essential for TNFα-induced IKK and NF-κB activation
c110 cso30:c:InputProcess connector
c116 cso30:c:InputProcess connector
c112 cso30:c:OutputProcess connector
p18_propro_p18
PMID: 18267068
Thus when IL-1R binds IL-1 or RIG-I binds cytoplasmic dsRNA they activate overlapping but unique signaling pathways due to these differences in upstream signaling components, and hence they induce distinct transcriptional programs.
c45 cso30:c:InputProcess connector
c46 cso30:c:InputProcess connector
c47 cso30:c:OutputProcess connector
p19_propro_p19
PMID: 18267068, 17047224
For example, IL-1R and RIG-I, which both signal through TRAF6 to IKK, do so through distinct receptor proximal adaptor components MyD88 and MAVS, respectively
c48 cso30:c:InputProcess connector
c49 cso30:c:InputProcess connector
c50 cso30:c:OutputProcess connector
p41_propro_p41
PMID: 18267068, 8565075, 9529147, 8947041, 10755617
RIP1 binds to NEMO and is essential for TNFα-induced IKK and NF-κB activation
c113 cso30:c:InputProcess connector
c114 cso30:c:OutputProcess connector
p42_propro_p42
PMID: 18267068, 11359906
In the absence of RIP1, IKK recruitment occurs through TRAF2 but does not lead to IKK activation
c115 cso30:c:InputProcess connector
c179 cso30:c:InputProcess connector
c117 cso30:c:OutputProcess connector
p43_propro_p43
PMID: 18267068, 16603398, 16543241
RIP1 is inducibly ubiquitinated by TRAF2 following TNFα stimulation.
PMID: 18267068, 16547522
RIP also becomes rapidly ubiquitinated following TNFα stimulation, and it has been proposed that it is through this posttranslational modification that RIP1 binds to NEMO.
c118 cso30:c:InputProcess connector
c119 cso30:c:OutputProcess connector
p44_propro_p44
PMID: 18267068, 15064760, 16115877
In addition to TNFR1 signaling, and IKK activation via other death domain-containing TNFR family members, RIP1 has also been reported to be required for TRIF-dependent NF-κB activation via TLR3 and TLR4, as well as for NF-κB activation via RIG-I
c120 cso30:c:InputProcess connector
c122 cso30:c:InputProcess connector
c121 cso30:c:OutputProcess connector
p45_propro_p45
PMID: 18267068, 15064760, 16115877
In addition to TNFR1 signaling, and IKK activation via other death domain-containing TNFR family members, RIP1 has also been reported to be required for TRIF-dependent NF-κB activation via TLR3 and TLR4, as well as for NF-κB activation via RIG-I
c123 cso30:c:InputProcess connector
c124 cso30:c:InputProcess connector
c125 cso30:c:OutputProcess connector
p46_propro_p46
PMID: 18267068, 15064760, 16115877
In addition to TNFR1 signaling, and IKK activation via other death domain-containing TNFR family members, RIP1 has also been reported to be required for TRIF-dependent NF-κB activation via TLR3 and TLR4, as well as for NF-κB activation via RIG-I
c127 cso30:c:InputProcess connector
c126 cso30:c:OutputProcess connector
p47_propro_p47
PMID: 18267068, 15064760, 16115877
In addition to TNFR1 signaling, and IKK activation via other death domain-containing TNFR family members, RIP1 has also been reported to be required for TRIF-dependent NF-κB activation via TLR3 and TLR4, as well as for NF-κB activation via RIG-I
c128 cso30:c:InputProcess connector
c129 cso30:c:InputProcess connector
c130 cso30:c:OutputProcess connector
p48_propro_p48
PMID: 18267068, 15064760, 16115877
In addition to TNFR1 signaling, and IKK activation via other death domain-containing TNFR family members, RIP1 has also been reported to be required for TRIF-dependent NF-κB activation via TLR3 and TLR4, as well as for NF-κB activation via RIG-I
c131 cso30:c:InputProcess connector
c132 cso30:c:InputProcess connector
c133 cso30:c:OutputProcess connector
p49_propro_p49
PMID: 18267068, 15064760, 16115877
In addition to TNFR1 signaling, and IKK activation via other death domain-containing TNFR family members, RIP1 has also been reported to be required for TRIF-dependent NF-κB activation via TLR3 and TLR4, as well as for NF-κB activation via RIG-I
c134 cso30:c:InputProcess connector
c136 cso30:c:InputAssociation connector
c135 cso30:c:OutputProcess connector
p50_propro_p50
PMID: 18267068, 15064760, 16115877
In addition to TNFR1 signaling, and IKK activation via other death domain-containing TNFR family members, RIP1 has also been reported to be required for TRIF-dependent NF-κB activation via TLR3 and TLR4, as well as for NF-κB activation via RIG-I
c137 cso30:c:InputProcess connector
c139 cso30:c:InputAssociation connector
c138 cso30:c:OutputProcess connector
p53_propro_p53
PMID: 18267068
Both BCL10 and CARD11 (CARMA1) are CARD-containing proteins that are crucial for IKK activation downstream of either the T cell or B cell antigen receptors.
PMID: 18267068, 17098202
The most notable feature of the BCL10, CARD11, MALT1 (CBM) complex is its induced oligomerization following signaling, which is thought to be a key event in IKK activation downstream of these CARD-containing adaptor proteins
c51 cso30:c:InputProcess connector
c194 cso30:c:InputAssociation connector
c55 cso30:c:OutputProcess connector
p54_propro_p54
PMID: 18267068
Members of the NOD-LRR family of intracellular pattern recognition receptors are CARD-containing proteins that can activate IKKβ via RIP2.
c149 cso30:c:InputProcess connector
c150 cso30:c:InputProcess connector
c151 cso30:c:OutputProcess connector
p55_propro_p55
PMID: 18267068, 10880512
RIP2 binds to NEMO and is believed to directly mediate activation of the IKK complex by proximity-induced mechanisms
c152 cso30:c:InputProcess connector
c111 cso30:c:InputProcess connector
c154 cso30:c:OutputProcess connector
p57_propro_p57
PMID: 18267068, 17047224
NIK directly phosphorylates and activates IKKα.
PMID: 18267068, 17047224, 17072322
The alternative pathway relies on the activation of IKKα by the NF-κB-inducing kinase (NIK).
PMID: 18267068
Active IKKβ is phosphorylated on two serines, Ser177 and Ser181, within the activation loop of the kinase domain, and IKKα is similarly phosphorylated on activation loop serine residues 176 and 180.
c157 cso30:c:InputProcess connector
c90 cso30:c:InputAssociation connector
c22 cso30:c:OutputProcess connector
p33_propro_p33
PMID: 18267068, 17996648, 18022362, 18022363
In addition to TRAF3, cIAP1 and cIAP2 have been implicated as E3 ligases responsible for regulating constitutive NIK levels
c95 cso30:c:InputProcess connector
c159 cso30:c:InputAssociation connector
c158 cso30:c:OutputProcess connector
p58_propro_p58
PMID: 18267068, 17996648, 18022362, 18022363
In addition to TRAF3, cIAP1 and cIAP2 have been implicated as E3 ligases responsible for regulating constitutive NIK levels
c160 cso30:c:InputProcess connector
c162 cso30:c:InputAssociation connector
c161 cso30:c:OutputProcess connector
p59_propro_p59
PMID: 18267068, 10823818
It appears that IKKα and IKKβ preferentially form heterodimers in vivo, and in vitro studies indicate that IKKα/IKKβ heterodimers have higher catalytic efficiency than either homodimer
c163 cso30:c:InputProcess connector
c165 cso30:c:InputProcess connector
c164 cso30:c:OutputProcess connector
p60_propro_p60
PMID: 18267068, 9346484, 9346485, 9346241
IKKα and IKKβ dimerize through the leucine zipper domain, which is also required for kinase activity.
c166 cso30:c:InputProcess connector
c167 cso30:c:OutputProcess connector
p61_propro_p61
PMID: 18267068, 9346484, 9346485, 9346241
IKKα and IKKβ dimerize through the leucine zipper domain, which is also required for kinase activity.
c168 cso30:c:InputProcess connector
c169 cso30:c:OutputProcess connector
p62_propro_p62
PMID: 18267068, 12244103, 10968790
IKKα and IKKβ bind NEMO through the C-terminal hexapeptide NEMO-binding domain (NBD) (Leu-Asp-Trp-Ser-Trp-Leu)
PMID: 18267068, 12244103
Competition experiments and biophysical analyses using the NBD peptide indicate that IKKβ binds to NEMO with considerably higher affinity than IKKα
c170 cso30:c:InputProcess connector
c171 cso30:c:InputProcess connector
c172 cso30:c:OutputProcess connector
p63_propro_p63
PMID: 18267068, 12244103, 10968790
IKKα and IKKβ bind NEMO through the C-terminal hexapeptide NEMO-binding domain (NBD) (Leu-Asp-Trp-Ser-Trp-Leu)
PMID: 18267068, 12244103
Competition experiments and biophysical analyses using the NBD peptide indicate that IKKβ binds to NEMO with considerably higher affinity than IKKα
c173 cso30:c:InputProcess connector
c174 cso30:c:InputProcess connector
c175 cso30:c:OutputProcess connector
p64_propro_p64
PMID: 18267068
Multiple lines of evidence point toward an IKK kinase complex that is composed of only IKKα, IKKβ, and NEMO.
PMID: 18267068, 17924664
Recombinant NEMO and IKKβ appear to associate in a 2:2 molar ratio and the minimum interaction domains form a dimer of dimers (tetramer) that can further assemble into octamers and dodecamers
c144 cso30:c:InputProcess connector
c176 cso30:c:InputProcess connector
c177 cso30:c:OutputProcess connector
p65_propro_p65
PMID: 18267068
The first is the kinase chaperone HSP-90/Cdc37 that has been reported to constitutively associate with the IKK complex.
c147 cso30:c:InputProcess connector
c185 cso30:c:InputProcess connector
c186 cso30:c:InputProcess connector
c180 cso30:c:OutputProcess connector
p66_propro_p66
PMID: 18267068, 11864612
The HSP-90 inhibitor geldanamycin has also been shown to inhibit activation of IKK by TNF-α
c181 cso30:c:InputProcess connector
c183 cso30:c:InputInhibitor connector
c184 cso30:c:InputAssociation connector
c182 cso30:c:OutputProcess connector
p67_propro_p67
PMID: 18267068, 15218148
The second interacting protein that requires mentioning is ELKS, which has been proposed to be a regulatory component of the IKK complex in addition to NEMO
c187 cso30:c:InputProcess connector
c188 cso30:c:InputProcess connector
c189 cso30:c:OutputProcess connector
p68_propro_p68
PMID: 18267068
Active IKKβ is phosphorylated on two serines, Ser177 and Ser181, within the activation loop of the kinase domain, and IKKα is similarly phosphorylated on activation loop serine residues 176 and 180.
c190 cso30:c:InputProcess connector
c191 cso30:c:OutputProcess connector
p69_propro_p69
PMID: 18267068
Both BCL10 and CARD11 (CARMA1) are CARD-containing proteins that are crucial for IKK activation downstream of either the T cell or B cell antigen receptors.
PMID: 18267068, 17098202
The most notable feature of the BCL10, CARD11, MALT1 (CBM) complex is its induced oligomerization following signaling, which is thought to be a key event in IKK activation downstream of these CARD-containing adaptor proteins
PMID: 18267068, 17098202
In AgR signaling the CBM complex also assembles into a higher-order oligomer following signaling.
c192 cso30:c:InputProcess connector
c140 cso30:c:InputAssociation connector
c141 cso30:c:InputAssociation connector
c193 cso30:c:OutputProcess connector
p51_propro_p51
PMID: 18267068, 15107419, 12612076, 17924664
NEMO can form tetramers in vitro and also is reported to oligomerize in vivo, although the stoichiometry of endogenous NEMO is debatable
c142 cso30:c:InputProcess connector
c143 cso30:c:OutputProcess connector
p52_propro_p52
PMID: 18267068
both IKKα and IKKβ phosphorylate IκBα at Ser32 and Ser36 and IκBβ at Ser19 and Ser23
PMID: 18267068, 9721103
IκBα bound to NF-κB is thought to be a preferred substrate to free IκBα
PMID: 18267068
both IKKα and IKKβ prefer IκBα to IκBβ, which is consistent with the difference in IκBα and β degradation
c178 cso30:c:InputAssociation connector
c19 cso30:c:InputProcess connector
c20 cso30:c:OutputProcess connector
p70_propro_p70
PMID: 18267068
both IKKα and IKKβ phosphorylate IκBα at Ser32 and Ser36 and IκBβ at Ser19 and Ser23
PMID: 18267068, 9721103
IκBα bound to NF-κB is thought to be a preferred substrate to free IκBα
PMID: 18267068
both IKKα and IKKβ prefer IκBα to IκBβ, which is consistent with the difference in IκBα and β degradation
c197 cso30:c:InputAssociation connector
c145 cso30:c:InputProcess connector
c148 cso30:c:OutputProcess connector
p71_propro_p71
PMID: 18267068
both IKKα and IKKβ phosphorylate IκBα at Ser32 and Ser36 and IκBβ at Ser19 and Ser23
PMID: 18267068
both IKKα and IKKβ prefer IκBα to IκBβ, which is consistent with the difference in IκBα and β degradation
c198 cso30:c:InputProcess connector
c202 cso30:c:InputAssociation connector
c199 cso30:c:OutputProcess connector
p72_propro_p72
PMID: 18267068
both IKKα and IKKβ phosphorylate IκBα at Ser32 and Ser36 and IκBβ at Ser19 and Ser23
PMID: 18267068
both IKKα and IKKβ prefer IκBα to IκBβ, which is consistent with the difference in IκBα and β degradation
c200 cso30:c:InputProcess connector
c203 cso30:c:InputAssociation connector
c201 cso30:c:OutputProcess connector
p73_propro_p73
PMID: 18267068
The nuclear NF-κB drives IκBα expression generating a negative feedback loop.
c205 cso30:c:InputAssociation connector
c204 cso30:c:OutputProcess connector
p74_propro_p74
PMID: 18267068
Like IκBα, IκBvar epsilon is degraded in an IKK-dependent manner and its expression is upregulated by NF-κB.
c206 cso30:c:InputAssociation connector
c207 cso30:c:OutputProcess connector
p75_propro_p75
PMID: 18267068, 8816457, 7867065
IκBβ is capable of associating with NF-κB dimers that are bound to DNA.
c208 cso30:c:InputProcess connector
c209 cso30:c:InputProcess connector
c210 cso30:c:OutputProcess connector
p76_propro_p76
PMID: 18267068, 17072324, 15371334
Multiple reports have demonstrated that IKKβ-dependent phosphorylation of the C-terminal region of p105 at Ser923 and Ser927 (Ser933 in human p105) leads to complete degradation of the protein analogous to IκBα
c211 cso30:c:InputProcess connector
c213 cso30:c:InputAssociation connector
c212 cso30:c:OutputProcess connector
p77_propro_p77
PMID: 18267068, 16619030
Normal processing of p105 to p50 in an E1 Ub-activating enzyme-deficient cell line, complemented by in vitro analysis, strongly suggests that p105 processing can occur via the 20S proteasome, independent of ubiquitination, and in a manner that is inconsistent with cotranslational processing
c214 cso30:c:InputProcess connector
c216 cso30:c:InputAssociation connector
c217 cso30:c:OutputProcess connector
c215 cso30:c:OutputProcess connector
p78_propro_p78
PMID: 18267068
Thus unprocessed p105 acts as an IκB protein that binds NF-κB dimers and can be inducibly degraded upon IKK activation.
c218 cso30:c:InputProcess connector
c220 cso30:c:InputProcess connector
c219 cso30:c:OutputProcess connector
p79_propro_p79
PMID: 18267068
Thus unprocessed p105 acts as an IκB protein that binds NF-κB dimers and can be inducibly degraded upon IKK activation.
c221 cso30:c:InputProcess connector
c222 cso30:c:OutputProcess connector
c223 cso30:c:OutputProcess connector
p80_propro_p80
PMID: 18267068, 11687592
Regulation of RelB by p100 is especially crucial because RelB-containing dimers only associate with p100, and it has been suggested that they require p100 binding for stabilization
c224 cso30:c:InputProcess connector
c225 cso30:c:InputProcess connector
c226 cso30:c:OutputProcess connector
p81_propro_p81
PMID: 18267068, 16303288, 12185077, 14676825
Phosphorylation of p100 at serines 866, 870, and 872 (Ser865, 869, and 871 in human p100) leads to the recruitment of SCFβTrCP, polyubiquitination of Lys855 in a region with sequence homology to Lys22 of IκBα, and subsequent degradation or processing to p52
c227 cso30:c:InputProcess connector
c228 cso30:c:InputProcess connector
c229 cso30:c:OutputProcess connector
p82_propro_p82
PMID: 18267068, 16303288, 12185077, 14676825
Phosphorylation of p100 at serines 866, 870, and 872 (Ser865, 869, and 871 in human p100) leads to the recruitment of SCFβTrCP, polyubiquitination of Lys855 in a region with sequence homology to Lys22 of IκBα, and subsequent degradation or processing to p52
c230 cso30:c:InputProcess connector
c231 cso30:c:OutputProcess connector
p83_propro_p83
PMID: 18267068
The noncanonical or alternative NF-κB pathway, however, proceeds through proteasomal processing, rather than degradation, of p100 to p52, thereby liberating p52 containing NF-κB dimers that drive a transcriptional response that is distinct from that induced by the canonical, IκBα-regulated pathway.
PMID: 18267068, 16303288, 12185077, 14676825
Phosphorylation of p100 at serines 866, 870, and 872 (Ser865, 869, and 871 in human p100) leads to the recruitment of SCFβTrCP, polyubiquitination of Lys855 in a region with sequence homology to Lys22 of IκBα, and subsequent degradation or processing to p52
c8 cso30:c:InputProcess connector
c232 cso30:c:OutputProcess connector
c233 cso30:c:OutputProcess connector
c234 cso30:c:OutputProcess connector
p4_propro_p4
PMID: 18267068, 17254973
In addition to IκBα/β/var epsilon, p100 can also act as a traditional IκB regulating p65-containing complexes downstream of IKKα
c9 cso30:c:InputProcess connector
c235 cso30:c:InputProcess connector
c236 cso30:c:OutputProcess connector
p7_propro_p7
PMID: 18267068, 17072328, 16470223
Because p100 undergoes constitutive processing in certain tissues, RelB/p52 heterodimers may exhibit constitutive activation and RelB-deficient mice have decreased baseline NF-κB activity in the thymus and spleen
c16 cso30:c:InputProcess connector
c17 cso30:c:InputProcess connector
c18 cso30:c:OutputProcess connector
p84_propro_p84
PMID: 18267068
Bcl-3 is found in the nucleus associated with p50- and p52-containing homo- and heterodimers.
c237 cso30:c:InputProcess connector
c238 cso30:c:InputProcess connector
c239 cso30:c:OutputProcess connector
p85_propro_p85
PMID: 18267068
Bcl-3 is found in the nucleus associated with p50- and p52-containing homo- and heterodimers.
c240 cso30:c:InputProcess connector
c241 cso30:c:InputProcess connector
c242 cso30:c:OutputProcess connector
p86_propro_p86
PMID: 18267068
Bcl-3 is found in the nucleus associated with p50- and p52-containing homo- and heterodimers.
PMID: 18267068, 17673665
Bcl-3 may also stabilize repressive p50 homodimers and inhibit NF-κB activation by preventing the access of TAD-containing dimers to κB sites
c243 cso30:c:InputProcess connector
c244 cso30:c:InputProcess connector
c245 cso30:c:OutputProcess connector
p87_propro_p87
PMID: 18267068, 12808109, 11713278
Cyclin D1 is a Bcl-3-regulated gene that is of particular interest owing to its role in cell proliferation and cancer.
c246 cso30:c:InputAssociation connector
c247 cso30:c:OutputProcess connector
p88_propro_p88
PMID: 18267068, 16384933
Bcl-3 has also recently been implicated in the regulation of p53 by enhancing the transcription of Hdm2 in normal and cancer cells
c249 cso30:c:InputAssociation connector
c248 cso30:c:OutputProcess connector
p89_propro_p89
PMID: 18267068, 15371334
IκBζ is not expressed constitutively but rather is upregulated in response to IL-1 and TLR4 ligands, but not TNF, and upon expression localizes to the nucleus
c252 cso30:c:InputAssociation connector
c251 cso30:c:OutputProcess connector
p90_propro_p90
PMID: 18267068, 15371334
IκBζ is not expressed constitutively but rather is upregulated in response to IL-1 and TLR4 ligands, but not TNF, and upon expression localizes to the nucleus
c253 cso30:c:InputAssociation connector
c250 cso30:c:OutputProcess connector
p91_propro_p91
PMID: 18267068, 15371334
IκBζ is not expressed constitutively but rather is upregulated in response to IL-1 and TLR4 ligands, but not TNF, and upon expression localizes to the nucleus
c255 cso30:c:InputAssociation connector
c258 cso30:c:InputAssociation connector
c254 cso30:c:OutputProcess connector
p92_propro_p92
PMID: 18267068, 15371334
IκBζ is not expressed constitutively but rather is upregulated in response to IL-1 and TLR4 ligands, but not TNF, and upon expression localizes to the nucleus
c257 cso30:c:InputAssociation connector
c259 cso30:c:InputAssociation connector
c256 cso30:c:OutputProcess connector
p93_propro_p93
PMID: 18267068, 15371334
IκBζ is not expressed constitutively but rather is upregulated in response to IL-1 and TLR4 ligands, but not TNF, and upon expression localizes to the nucleus
c260 cso30:c:InputProcess connector
c261 cso30:c:OutputProcess connector
p94_propro_p94
PMID: 18267068
IκBζ is inducibly expressed following NF-κB activation and once expressed associates primarily with p50 homodimers.
c262 cso30:c:InputProcess connector
c263 cso30:c:InputProcess connector
c264 cso30:c:OutputProcess connector
p95_propro_p95
PMID: 18267068, 15241416
IκBζ is found associated with p50 on the promoter of IL-6, which is not inducibly expressed in IκBζ knockout cells, and it is, therefore, hypothesized that IκBζ acts as a coactivator for p50 homodimers
c265 cso30:c:InputProcess connector
c267 cso30:c:InputProcess connector
c268 cso30:c:InputProcess connector
c266 cso30:c:OutputProcess connector
p96_propro_p96
PMID: 18267068, 9660950
PKA exists in a complex with cytosolic NF-κB:IκB complexes and following degradation of IκBα phosphorylates p65 at Ser276, promoting the interaction of p65 with the transcriptional coactivators CBP (CREB-binding protein) and p300
c31 cso30:c:InputProcess connector
c32 cso30:c:OutputProcess connector
p97_propro_p97
PMID: 18267068
In addition to PKA, other kinases, most notably MSK1 and MSK2 (mitogen- and stress-activated protein kinase), have been reported to phosphorylate Ser276 of p65.
c273 cso30:c:InputProcess connector
c275 cso30:c:InputAssociation connector
c274 cso30:c:OutputProcess connector
p98_propro_p98
PMID: 18267068
In addition to PKA, other kinases, most notably MSK1 and MSK2 (mitogen- and stress-activated protein kinase), have been reported to phosphorylate Ser276 of p65.
c276 cso30:c:InputProcess connector
c278 cso30:c:InputAssociation connector
c277 cso30:c:OutputProcess connector
p99_propro_p99
PMID: 18267068, 15122352, 17072324
IKKα and IKKβ have been implicated in the direct phosphorylation of p65 at Ser536
c37 cso30:c:InputProcess connector
c280 cso30:c:InputProcess connector
c281 cso30:c:InputAssociation connector
p100_propro_p100
PMID: 18267068, 15122352, 17072324
IKKα and IKKβ have been implicated in the direct phosphorylation of p65 at Ser536
c282 cso30:c:InputProcess connector
c284 cso30:c:InputAssociation connector
c283 cso30:c:OutputProcess connector
p101_propro_p101
PMID: 18267068, 9405476, 10938077
Ser529 of p65 may also be inducibly phosphorylated by CK2 following IL-1 or TNF-α stimulation, although it is unclear whether Ser529 phosphorylation affects transcription
c285 cso30:c:InputProcess connector
c287 cso30:c:InputAssociation connector
c286 cso30:c:OutputProcess connector
p102_propro_p102
PMID: 18267068, 12881425
PKCζ can phosphorylate p65 at Ser311, and CBP fails to associate with p65 following stimulation of PKCζ-deficient cells
c288 cso30:c:InputProcess connector
c290 cso30:c:InputAssociation connector
c289 cso30:c:OutputProcess connector
p103_propro_p103
PMID: 18267068, 9660950
PKA exists in a complex with cytosolic NF-κB:IκB complexes and following degradation of IκBα phosphorylates p65 at Ser276, promoting the interaction of p65 with the transcriptional coactivators CBP (CREB-binding protein) and p300.
PMID: 18267068, 17434128
It was recently reported that IKKα phosphorylates CBP in a stimulus-dependent manner, inducing upregulation of CBP activity, increased binding to p65, and decreased binding to p53
c291 cso30:c:InputProcess connector
c293 cso30:c:InputProcess connector
c309 cso30:c:InputProcess connector
c294 cso30:c:OutputProcess connector
p104_propro_p104
PMID: 18267068, 15122352
Acetylation of p65, probably by CBP/p300 and associated HATs, occurs in the nucleus and is associated with increased transcription
PMID: 18267068
p65 phosphorylation is necessary to recruit CBP/p300 allowing acetylation at Lys310
c295 cso30:c:InputProcess connector
c296 cso30:c:OutputProcess connector
p105_propro_p105
PMID: 18267068, 16382138
One possibility is that Ser536 phosphorylation alters the interaction of p65 with the SMRT (silencing mediator of retinoic acid and thyroid hormone receptor) corepressor complex such that the level of HDAC3 is decreased and CBP/p300 is increased.
c297 cso30:c:InputProcess connector
c298 cso30:c:InputProcess connector
c300 cso30:c:InputProcess connector
c299 cso30:c:OutputProcess connector
p106_propro_p106
PMID: 18267068, 16382138
In addition to p65 phosphorylation, IKKα also may promote Lys310 acetylation through direct phosphorylation of SMRT, which leads to displacement of HDAC3 from the SMRT corepressor complex.
c301 cso30:c:InputProcess connector
c303 cso30:c:InputAssociation connector
c302 cso30:c:OutputProcess connector
p107_propro_p107
PMID: 18267068, 12789343, 12789342
IKKα is found associated with the κB sites of some NF-κB-responsive genes, and stimulus-induced phosphorylation of histone H3 on serine 10 does not occur in the absence of IKKα
c304 cso30:c:InputProcess connector
c306 cso30:c:InputAssociation connector
c305 cso30:c:OutputProcess connector
p108_propro_p108
PMID: 18267068, 17434128
In addition to the SMRT and N-CoR (nuclear receptor corepressor) complexes, IKKα also has been shown to phosphorylate the CBP coactivator
c292 cso30:c:InputProcess connector
c308 cso30:c:InputAssociation connector
c307 cso30:c:OutputProcess connector
p109_propro_p109
p110_propro_p110
PMID: 18267068, 16382138
In addition to p65 phosphorylation, IKKα also may promote Lys310 acetylation through direct phosphorylation of SMRT, which leads to displacement of HDAC3 from the SMRT corepressor complex.
c310 cso30:c:InputProcess connector
c311 cso30:c:OutputProcess connector
c312 cso30:c:OutputProcess connector
p111_propro_p111
PMID: 18267068
Figure.4
c313 cso30:c:InputInhibitor connector
p112_propro_p112
PMID: 18267068, 17434128
It was recently reported that IKKα phosphorylates CBP in a stimulus-dependent manner, inducing upregulation of CBP activity, increased binding to p65, and decreased binding to p53
c315 cso30:c:InputProcess connector
c316 cso30:c:InputProcess connector
c317 cso30:c:InputInhibitor connector
c314 cso30:c:OutputProcess connector
p113_propro_p113
PMID: 18267068, 16007092
GSK3β, normally constitutively active, phosphorylates and inactivates CREB disrupting the interaction between CREB and CBP
c318 cso30:c:InputProcess connector
c320 cso30:c:InputAssociation connector
c319 cso30:c:OutputProcess connector
p114_propro_p114
PMID: 18267068, 16007092
GSK3β, normally constitutively active, phosphorylates and inactivates CREB disrupting the interaction between CREB and CBP
c321 cso30:c:InputProcess connector
c322 cso30:c:InputProcess connector
c324 cso30:c:InputInhibitor connector
c323 cso30:c:OutputProcess connector
p115_propro_p115
PMID: 18267068
One potential explanation is that CBP bound to CREB is a poor substrate for IKKα phosphorylation, and that CBP phosphorylated by IKKα binds poorly to CREB.
c325 cso30:c:InputProcess connector
c326 cso30:c:InputProcess connector
c327 cso30:c:OutputProcess connector
p116_propro_p116
PMID: 18267068, 18045535
One recent and intriguing addition to this list is ribosomal protein S3 (RPS3), which seems to be required for the binding of NF-κB at specific κB sites
c328 cso30:c:InputProcess connector
c329 cso30:c:InputProcess connector
c330 cso30:c:OutputProcess connector
p117_propro_p117
PMID: 18267068, 17377533
IKKα represses transcription of the tumor suppressor Maspin by acting at the maspin promoter strongly supports a direct mechanism of action by IKKα that is independent of NF-κB
c331 cso30:c:InputInhibitor connector
c332 cso30:c:OutputProcess connector
p118_propro_p118
PMID: 18267068, 17183367
Although the exact mechanism of action remains unclear, it has recently been shown that targeting the SOCS-1-containing ubiquitin ligase complex (ECSSOCS1) to p65-containing dimers is carried out by COMMD1 (Copper Metabolism MURR1 Domain containing-1) proteins
c333 cso30:c:InputProcess connector
c334 cso30:c:InputProcess connector
c335 cso30:c:InputProcess connector
c336 cso30:c:OutputProcess connector
p119_propro_p119
PMID: 18267068, 15858576, 16116086
IKKα is also involved in termination of inflammatory transcriptional responses in macrophages, possibly by promoting the nuclear degradation of both p65 and c-Rel
c337 cso30:c:InputProcess connector
c340 cso30:c:InputAssociation connector
c338 cso30:c:OutputProcess connector
c339 cso30:c:OutputProcess connector
p120_propro_p120
PMID: 18267068, 15858576, 16116086
IKKα is also involved in termination of inflammatory transcriptional responses in macrophages, possibly by promoting the nuclear degradation of both p65 and c-Rel
c341 cso30:c:InputProcess connector
c343 cso30:c:InputAssociation connector
c342 cso30:c:OutputProcess connector
p121_propro_p121
PMID: 18267068, 16547522
RIP also becomes rapidly ubiquitinated following TNFα stimulation, and it has been proposed that it is through this posttranslational modification that RIP1 binds to NEMO.
c344 cso30:c:InputProcess connector
c345 cso30:c:InputProcess connector
c346 cso30:c:OutputProcess connector
p122_propro_p122
PMID: 18267068
Conformational changes in the IKK complex induced by binding of NEMO to RIP, and/or ubiquitination of NEMO, lead to the exposure of IKK kinase domain and T loop serines and consequent transautophosphorylation or phosphorylation by an IKK-K such as TAK1.
c347 cso30:c:InputProcess connector
c348 cso30:c:OutputProcess connector
p123_propro_p123
PMID: 18267068
Conformational changes in the IKK complex induced by binding of NEMO to RIP, and/or ubiquitination of NEMO, lead to the exposure of IKK kinase domain and T loop serines and consequent transautophosphorylation or phosphorylation by an IKK-K such as TAK1.
c349 cso30:c:InputProcess connector
c352 cso30:c:InputAssociation connector
c350 cso30:c:OutputProcess connector
c351 cso30:c:OutputProcess connector
p124_propro_p124
PMID: 18267068
The active IKK then phosphorylates downstream substrates, including serine 740 within the IKK NBD and serine 68 in NEMO.
c353 cso30:c:InputProcess connector
c354 cso30:c:OutputProcess connector
p125_propro_p125
PMID: 18267068
NEMO phosphorylation results in the separation of stable NEMO dimers and NEMO binding to IKK.
c355 cso30:c:InputProcess connector
c356 cso30:c:OutputProcess connector
c357 cso30:c:OutputProcess connector
c358 cso30:c:OutputProcess connector
p126_propro_p126
PMID: 18267068, 16126728, 17188031
the protein phosphatase 2A (PP2A) has been shown to associate with IKK and potentiate IKK activation in cells
c359 cso30:c:InputProcess connector
c360 cso30:c:InputProcess connector
c361 cso30:c:OutputProcess connector
p127_propro_p127
PMID: 18267068, 16126728, 14585847, 17977820
structural changes induced by NEMO Ser68 and IKK NBD phosphorylation may allow dephosphorylation of the activation loop serines in IKKs as well as N-terminal phosphorylation sites in NEMO by PP2A or PP2Cβ
c362 cso30:c:InputProcess connector
c363 cso30:c:OutputProcess connector
p128_propro_p128
PMID: 18267068, 17947236, 18079694, 17277144
Similar to RIP1, the kinase activity of RIP2 does not appear to be required, and RIP2 is also ubiquitinated through the action of Ubc13/TRAF6
c366 cso30:c:InputAssociation connector
c367 cso30:c:InputAssociation connector
c364 cso30:c:InputProcess connector
c365 cso30:c:OutputProcess connector
p129_propro_p129
PMID: 18267068, 17562858, 17965022
RIP2 acts with TAK1 and TRAFs to induce NEMO ubiquitination and downstream signaling pathways
c368 cso30:c:InputProcess connector
c155 cso30:c:InputAssociation connector
c156 cso30:c:InputAssociation connector
c369 cso30:c:OutputProcess connector
p50:p65_enti_e5
p50:p65
Ikappa-Balpha:p50:p65_enti_e6
Ikappa-Balpha:p50:p65
IkappaB-alpha_enti_MO000000233
IkappaB-alpha
Ikappa-Balpha:p50:p65_enti_e11
Ikappa-Balpha:p50:p65
p100{p}_enti_MO000000202
p100{p}
p52_enti_MO000000196
p52
p52:p52_enti_MO000016637
p52:p52
DNA_enti_e12
DNA
DNA:p52:p52_enti_e13
DNA:p52:p52
RelA-p65_enti_MO000000193
RelA-p65
RelA-p65:p100_enti_e14
RelA-p65:p100
p100_enti_e16
p100
SCF-betaTrCP_enti_MO000018837
SCF-betaTrCP
UbcH5_enti_e18
UbcH5
protein remnants_enti_MO000019479
protein remnants
p50:p65{p}_enti_e20
p50:p65{p}
genes_enti_e21
genes
DNA:p50:p65_enti_e22
DNA:p50:p65
IL-1_enti_MO000000214
IL-1
IL-1:IL-1R_enti_e23
IL-1:IL-1R
IL-1R_enti_e24
IL-1R
MyD88_enti_MO000016573
MyD88
IL-1:IL-1R:MYD88_enti_e25
IL-1:IL-1R:MYD88
TNF-alpha_enti_MO000000289
TNF-alpha
TNF-alpha:TNFR1_enti_e29
TNF-alpha:TNFR1
TNFR1_enti_MO000000206
TNFR1
TRADD_enti_MO000000207
TRADD
TNF-alpha:TNFR1:TRADD_enti_e30
TNF-alpha:TNFR1:TRADD
TRAF2_enti_MO000000209
TRAF2
TNF-alpha:TNFR1:TRADD:TRAF2_enti_e31
TNF-alpha:TNFR1:TRADD:TRAF2
TRAF5_enti_MO000016965
TRAF5
TNF-alpha:TNFR1:TRADD:TRAF5_enti_e32
TNF-alpha:TNFR1:TRADD:TRAF5
IL-1:IL-1R:MYD88:Traf6_enti_e33
IL-1:IL-1R:MYD88:Traf6
TRAF6_enti_MO000000212
TRAF6
LPS_enti_MO000016882
LPS
TLR4_enti_MO000019394
TLR4
LPS:TLR4_enti_e34
LPS:TLR4
LPS:TLR4:MYD88_enti_e35
LPS:TLR4:MYD88
LPS:TLR4:MYD88:TRAF6_enti_e36
LPS:TLR4:MYD88:TRAF6
ligand:receptor complex_enti_e37
ligand:receptor complex
TRAF3_enti_MO000016963
TRAF3
ligand:receptor complex:TRAF3_enti_e38
ligand:receptor complex:TRAF3
IKK-alpha_enti_e39
IKK-alpha
NIK_enti_MO000000203
NIK
ligand:receptor complex:TRAF3:NIK_enti_e40
ligand:receptor complex:TRAF3:NIK
NIK{ub}_enti_e41
NIK{ub}
ligand:receptor complex:TRAF3{ub}:NIK_enti_e42
ligand:receptor complex:TRAF3{ub}:NIK
RIP1_enti_MO000000065
RIP1
TNF-alpha:TNFR1:TRADD:RIP1:TRAF2_enti_e43
TNF-alpha:TNFR1:TRADD:RIP1:TRAF2
MAVS_enti_MO000094908
MAVS
dsRNA_enti_MO000022224
dsRNA
DDX58_enti_MO000066987
DDX58
dsRNA:DDX58:MAVS_enti_e27
dsRNA:DDX58:MAVS
dsRNA:DDX58_enti_e26
dsRNA:DDX58
TNF-alpha:TNFR1:TRADD:RIP1:IKK_enti_e44
TNF-alpha:TNFR1:TRADD:RIP1:IKK
TNF-alpha:TNFR1:TRADD:RIP1:IKK{active}_enti_e45
TNF-alpha:TNFR1:TRADD:RIP1:IKK{active}
TNF-alpha:TNFR1:TRADD:TRAF2:IKK_enti_e46
TNF-alpha:TNFR1:TRADD:TRAF2:IKK
TNF-alpha:TNFR1:TRADD:RIP1{ub}:TRAF2_enti_e47
TNF-alpha:TNFR1:TRADD:RIP1{ub}:TRAF2
LPS:TLR4:TRIF_enti_e48
LPS:TLR4:TRIF
TRIF_enti_MO000041125
TRIF
LPS:TLR4:TRIF:RIP1_enti_e49
LPS:TLR4:TRIF:RIP1
dsRNA:TLR3_enti_e63
dsRNA:TLR3
dsRNA:TLR3:TRIF_enti_e64
dsRNA:TLR3:TRIF
dsRNA:TLR3:TRIF:RIP1_enti_e65
dsRNA:TLR3:TRIF:RIP1
NF-kappaB_enti_MO000000058
NF-kappaB
NF-kappaB{active}_enti_e67
NF-kappaB{active}
ligand:TCR complex_enti_e68
ligand:TCR complex
ligand:BCR complex_enti_e69
ligand:BCR complex
CBM complex_enti_e70
CBM complex
NOD:ligand complex_enti_e72
NOD:ligand complex
RIP2_enti_MO000017949
RIP2
NOD:ligand:RIP2_enti_e73
NOD:ligand:RIP2
NOD:ligand:RIP2:IKK_enti_e74
NOD:ligand:RIP2:IKK
NOD:ligand:RIP2:IKK_enti_e75
NOD:ligand:RIP2:IKK
IKK-alpha{p}_enti_MO000038331
IKK-alpha{p}
cIAP-1_enti_MO000017874
cIAP-1
cIAP-2_enti_MO000017875
cIAP-2
IKK-alpha:IKK-beta_enti_MO000033291
IKK-alpha:IKK-beta
IKK-alpha:IKK-beta:(IKK-gamma)n_enti_MO000016661
IKK-alpha:IKK-beta:(IKK-gamma)n
IKK-beta_enti_MO000000211
IKK-beta
(IKK-alpha)2_enti_e66
(IKK-alpha)2
(IKK-beta)2_enti_e76
(IKK-beta)2
IKK-gamma_enti_MO000016599
IKK-gamma
IKK-beta:IKK-gamma_enti_e77
IKK-beta:IKK-gamma
IKK-alpha:IKK-gamma_enti_e78
IKK-alpha:IKK-gamma
IKK-alpha:IKK-beta:(IKK-gamma)n_enti_e79
IKK-alpha:IKK-beta:(IKK-gamma)n
IKK-alpha:IKK-beta:(IKK-gamma)2:Cdc37:Hsp-90_enti_e28
IKK-alpha:IKK-beta:(IKK-gamma)2:Cdc37:Hsp-90
geladanamycin_enti_e80
geladanamycin
Hsp90_enti_MO000021135
Hsp90
Hsp50_enti_MO000021134
Hsp50
ELKS_enti_MO000065270
ELKS
IKK-alpha:IKK-beta:(IKK-gamma)2:ELKS_enti_e81
IKK-alpha:IKK-beta:(IKK-gamma)2:ELKS
IKK-beta{p}_enti_e82
IKK-beta{p}
CBM oligomer_enti_e83
CBM oligomer
(IKK-gamma)n_enti_e71
(IKK-gamma)n
IkappaB-beta_enti_MO000000234
IkappaB-beta
IkappaB-beta{p}_enti_e84
IkappaB-beta{p}
IkappaB-alpha_enti_e85
IkappaB-alpha
IkappaB-epsilon_enti_e86
IkappaB-epsilon
IkappaB-beta_enti_e87
IkappaB-beta
DNA:p50:p65:IkappaB-beta_enti_e88
DNA:p50:p65:IkappaB-beta
p105_enti_MO000000199
p105
p105{p}_enti_MO000081711
p105{p}
20S proteasome_enti_MO000000291
20S proteasome
p50_enti_MO000000200
p50
p105:NF-kappaB_enti_e89
p105:NF-kappaB
(RelB)2_enti_e90
(RelB)2
p100:(RelB)2_enti_e91
p100:(RelB)2
p100{p}:SCF-betaTRCP_enti_e92
p100{p}:SCF-betaTRCP
p100{p}{ub}:SCF-betaTRCP_enti_e93
p100{p}{ub}:SCF-betaTRCP
p52:(RelB)2_enti_e94
p52:(RelB)2
Bcl-3_enti_MO000000238
Bcl-3
p52:p52:BCL3_enti_e95
p52:p52:BCL3
BCL3:p50:p65_enti_e96
BCL3:p50:p65
(p50)2_enti_MO000016636
(p50)2
(p50)2:BCL3_enti_e97
(p50)2:BCL3
Cyclin D1_enti_e98
Cyclin D1
Hdm2_enti_e99
Hdm2
IkappaB-zeta_enti_e100
IkappaB-zeta
IkappaB-zeta_enti_e101
IkappaB-zeta
IkappaB-zeta_enti_e102
IkappaB-zeta
(p50)2:IkappaB-zeta_enti_e103
(p50)2:IkappaB-zeta
IL-6_enti_e104
IL-6
IL-6:(p50)2:IkappaB-zeta_enti_e105
IL-6:(p50)2:IkappaB-zeta
PKAc_enti_MO000000001
PKAc
Ikappa-Balpha:p50:p65:PKAc_enti_e106
Ikappa-Balpha:p50:p65:PKAc
Ikappa-Balpha{p}:p50:p65:PKAc_enti_e107
Ikappa-Balpha{p}:p50:p65:PKAc
Ikappa-Balpha{p}{ub}:p50:p65:PKAc_enti_e15
Ikappa-Balpha{p}{ub}:p50:p65:PKAc
PKAc:p65:p50_enti_e17
PKAc:p65:p50
PKAc:p65{p}:p50_enti_e19
PKAc:p65{p}:p50
p50:p65{p}_enti_e108
p50:p65{p}
MSK1_enti_MO000019013
MSK1
MSK2_enti_e109
MSK2
CKII_enti_MO000017396
CKII
PKCzeta_enti_MO000016647
PKCzeta
CBP_enti_MO000017462
CBP
p300_enti_MO000019984
p300
p50:p65{p}:CBP:p300_enti_e110
p50:p65{p}:CBP:p300
p50:p65{p}{ace}:CBP:p300_enti_e111
p50:p65{p}{ace}:CBP:p300
p50:p65_enti_e112
p50:p65
SMRT_enti_MO000031185
SMRT
HDAC3_enti_MO000023574
HDAC3
p50:p65:SMRT:HDAC3_enti_e113
p50:p65:SMRT:HDAC3
IKK-alpha_enti_e114
IKK-alpha
p50:p65:SMRT{p}:HDAC3_enti_e115
p50:p65:SMRT{p}:HDAC3
Histone H3:DNA_enti_e116
Histone H3:DNA
Histone H3{p}:DNA_enti_e117
Histone H3{p}:DNA
CBP{p}_enti_e118
CBP{p}
p50:p65:SMRT{p}_enti_e119
p50:p65:SMRT{p}
p53:CBP_enti_e120
p53:CBP
p53_enti_MO000000277
p53
CREB_enti_MO000017189
CREB
CREB{p}_enti_e121
CREB{p}
GSK3beta_enti_MO000017332
GSK3beta
CREB:CBP_enti_e122
CREB:CBP
CREB:CBP{p}_enti_e123
CREB:CBP{p}
RPS3_enti_MO000069621
RPS3
p50:p65:RPS3_enti_e124
p50:p65:RPS3
SERPINB5_enti_G028758
SERPINB5
COMMD1_enti_e125
COMMD1
ECS-SOCS1_enti_e126
ECS-SOCS1
p50:p65:COMMD1:ECS-SOCS1_enti_e127
p50:p65:COMMD1:ECS-SOCS1
protein remnants_enti_e128
protein remnants
p50_enti_e129
p50
c-Rel_enti_MO000000192
c-Rel
TNF-alpha:TNFR1:TRADD:TRAF2IKK complex:RIP1{ub}_enti_e130
TNF-alpha:TNFR1:TRADD:TRAF2IKK complex:RIP1{ub}
RIP1{ub}:Nemo{ub}:TRAF2:TRAdd:TNFR1:TNF_enti_e131
RIP1{ub}:Nemo{ub}:TRAF2:TRAdd:TNFR1:TNF
IKK-alpha:IKK-beta:(IKK-gamma)n {p}_enti_e132
IKK-alpha:IKK-beta:(IKK-gamma)n {p}
TAK1_enti_MO000016574
TAK1
IKK-alpha:IKK-beta:(IKK-gamma)n {p}_enti_e133
IKK-alpha:IKK-beta:(IKK-gamma)n {p}
PP2A_enti_MO000016752
PP2A
IKK-alpha{p}:IKK-beta{p}_enti_e134
IKK-alpha{p}:IKK-beta{p}
PP2a:IKK-alpha{p}:IKK-beta{p}_enti_e135
PP2a:IKK-alpha{p}:IKK-beta{p}
PP2a:IKK-alpha:IKK-beta_enti_e136
PP2a:IKK-alpha:IKK-beta
Ubc13_enti_MO000022136
Ubc13
NOD ligand complex:RIP2{ub}_enti_e138
NOD ligand complex:RIP2{ub}
TRAFs_enti_e137
TRAFs