_enti_e9
_enti_e1
_enti_e10
_enti_e4
_enti_e2
_enti_e3
_enti_e55
_enti_e59
_enti_e53
_enti_e52
_enti_e50
_enti_e51
_enti_e54
_enti_e56
_enti_e58
_enti_e57
_enti_e61
_enti_e62
_enti_e60
g1_fact_g1
g2_fact_g13
g1_fact_g14
g4_fact_g4
g3_fact_g3
p1_propro_p1
PMID: 17349209
p50 is generated from limited proteasomal processing of the p105 protein as is p52 from the p100 protein.
c1 cso30:c:InputProcess connector
c2 cso30:c:OutputProcess connector
p4_propro_p4
PMID: 17349209
Activation of the IKK complex induces phosphorylation of the IκB proteins, leading to their K48-polyubiquitination and proteasomal degradation.
c7 cso30:c:InputProcess connector
c9 cso30:c:InputAssociation connector
c8 cso30:c:OutputProcess connector
p5_propro_p5
PMID: 17349209
Activation of the IKK complex induces phosphorylation of the IκB proteins, leading to their K48-polyubiquitination and proteasomal degradation.
c10 cso30:c:InputProcess connector
c11 cso30:c:OutputProcess connector
p6_propro_p6
PMID: 17349209
Activation of the IKK complex induces phosphorylation of the IκB proteins, leading to their K48-polyubiquitination and proteasomal degradation.
c12 cso30:c:InputProcess connector
c13 cso30:c:OutputProcess connector
c14 cso30:c:OutputProcess connector
p7_propro_p7
PMID: 17349209
The degradation of IκB protein allows for translocation of the liberated NF-κB dimers to the nucleus where they bind their cognate sites in DNA and activate gene transcription.
c58 cso30:c:InputProcess connector
c16 cso30:c:OutputProcess connector
p8_propro_p8
PMID: 17349209
The degradation of IκB protein allows for translocation of the liberated NF-κB dimers to the nucleus where they bind their cognate sites in DNA and activate gene transcription.
c17 cso30:c:InputProcess connector
c18 cso30:c:InputProcess connector
c19 cso30:c:OutputProcess connector
p9_propro_p9
PMID: 17349209
The degradation of IκB protein allows for translocation of the liberated NF-κB dimers to the nucleus where they bind their cognate sites in DNA and activate gene transcription.
c20 cso30:c:InputAssociation connector
c21 cso30:c:OutputProcess connector
p3_propro_p3
PMID: 17349209
Activation of the IKK complex induces phosphorylation of the IκB proteins, leading to their K48-polyubiquitination and proteasomal degradation.
c5 cso30:c:InputProcess connector
c6 cso30:c:OutputProcess connector
p10_propro_p10
PMID: 17349209, 16987664
In addition to interacting with IKKα and IKKβ, IKKγ/NEMO also interacts with a number of proteins associated with NF-κB activation including RIP and A20.
c22 cso30:c:InputProcess connector
c23 cso30:c:InputProcess connector
c24 cso30:c:InputProcess connector
c25 cso30:c:OutputProcess connector
p11_propro_p11
PMID: 17349209, 16987664
In addition to interacting with IKKα and IKKβ, IKKγ/NEMO also interacts with a number of proteins associated with NF-κB activation including RIP and A20.
c26 cso30:c:InputProcess connector
c27 cso30:c:InputProcess connector
c28 cso30:c:OutputProcess connector
p12_propro_p12
PMID: 17349209, 16987664
In addition to interacting with IKKα and IKKβ, IKKγ/NEMO also interacts with a number of proteins associated with NF-κB activation including RIP and A20.
c29 cso30:c:InputProcess connector
c30 cso30:c:InputProcess connector
c31 cso30:c:OutputProcess connector
p13_propro_p13
PMID: 17349209
The phosphorylation of IKKγ/NEMO has been reported to occur following TNF-α and IL-1 stimulation and appears to negatively regulate IKK activity.
PMID: 17349209, 12657630, 11971901
The phosphorylation occurs primarily on serine 376 and is IKKβ dependent, indicating that this may be an autoregulatory mechanism.
c32 cso30:c:InputProcess connector
c37 cso30:c:InputAssociation connector
c61 cso30:c:InputAssociation connector
c33 cso30:c:OutputProcess connector
p16_propro_p16
PMID: 17349209
The phosphorylation of IKKγ/NEMO has been reported to occur following TNF-α and IL-1 stimulation and appears to negatively regulate IKK activity.
c41 cso30:c:InputProcess connector
c43 cso30:c:InputAssociation connector
c62 cso30:c:InputAssociation connector
c42 cso30:c:OutputProcess connector
p17_propro_p17
PMID: 17349209
The polyubiquitination of IKKγ/NEMO occurs through K63-linked chains and does not target the protein for degradation but instead appears to serve as a posttranslational modification signal rather like phosphorylation.
PMID: 17349209, 16497931
In the case of NEMO, sumolyation induces its nuclear localisation and interaction with the DNA damage sensor ATM which then triggers IKKγ/NEMO mono-ubiquitination and nuclear export.
c44 cso30:c:InputProcess connector
c45 cso30:c:OutputProcess connector
p18_propro_p18
PMID: 17349209, 14651848
The sumolyation of IKKγ/NEMO has been identified as an important mechanism for the activation of NF-κB in response to genotoxic stress
c46 cso30:c:InputProcess connector
c47 cso30:c:OutputProcess connector
p19_propro_p19
PMID: 17349209, 16497931
In the case of NEMO, sumolyation induces its nuclear localisation and interaction with the DNA damage sensor ATM which then triggers IKKγ/NEMO mono-ubiquitination and nuclear export.
c48 cso30:c:InputProcess connector
c49 cso30:c:OutputProcess connector
p20_propro_p20
PMID: 17349209, 16497931
In the case of NEMO, sumolyation induces its nuclear localisation and interaction with the DNA damage sensor ATM which then triggers IKKγ/NEMO mono-ubiquitination and nuclear export.
c50 cso30:c:InputProcess connector
c51 cso30:c:InputProcess connector
c52 cso30:c:OutputProcess connector
p21_propro_p21
PMID: 17349209, 16497931
In the case of NEMO, sumolyation induces its nuclear localisation and interaction with the DNA damage sensor ATM which then triggers IKKγ/NEMO mono-ubiquitination and nuclear export.
c53 cso30:c:InputProcess connector
c54 cso30:c:OutputProcess connector
p22_propro_p22
PMID: 17349209
The cytoplasmic IKKγ/NEMO and ATM complex then activates the IKK complex and NF-κB through an unknown mechanism.
c55 cso30:c:InputProcess connector
c57 cso30:c:InputAssociation connector
c56 cso30:c:OutputProcess connector
p23_propro_p23
PMID: 17349209
The cytoplasmic IKKγ/NEMO and ATM complex then activates the IKK complex and NF-κB through an unknown mechanism.
c15 cso30:c:InputProcess connector
c60 cso30:c:InputAssociation connector
c59 cso30:c:OutputProcess connector
p24_propro_p24
PMID: 17349209, 2691328, 7867065, 1340770
IκBα and IκBβ preferentially bind c-Rel and p65 containing dimers.
c63 cso30:c:InputProcess connector
c64 cso30:c:InputProcess connector
c65 cso30:c:OutputProcess connector
p25_propro_p25
PMID: 17349209, 2691328, 7867065, 1340770
IκBα and IκBβ preferentially bind c-Rel and p65 containing dimers.
c66 cso30:c:InputProcess connector
c68 cso30:c:InputProcess connector
c67 cso30:c:OutputProcess connector
p26_propro_p26
PMID: 17349209, 2691328, 7867065, 1340770
IκBα and IκBβ preferentially bind c-Rel and p65 containing dimers.
c69 cso30:c:InputProcess connector
c70 cso30:c:InputProcess connector
c71 cso30:c:OutputProcess connector
p27_propro_p27
PMID: 17349209, 2691328, 7867065, 1340770
IκBα and IκBβ preferentially bind c-Rel and p65 containing dimers.
c72 cso30:c:InputProcess connector
c73 cso30:c:InputProcess connector
c74 cso30:c:OutputProcess connector
p29_propro_p29
PMID: 17349209, 8336935, 8497270
Bcl-3 binds only p50 and p52 homodimers.
c78 cso30:c:InputProcess connector
c79 cso30:c:InputProcess connector
c80 cso30:c:OutputProcess connector
p30_propro_p30
PMID: 17349209, 8336935, 8497270
Bcl-3 binds only p50 and p52 homodimers.
c81 cso30:c:InputProcess connector
c82 cso30:c:InputProcess connector
c83 cso30:c:OutputProcess connector
p31_propro_p31
PMID: 17349209, 17027520
IκBζ binds both p50 homodimers and p65/p50 dimers.
PMID: 17349209, 15241416
IκBζ is itself a TLR inducible gene which associates with p50 and is critical for the induction of the pro-inflammatory cytokines IL-6 and IL-12 following TLR stimulation in macrophages.
c84 cso30:c:InputProcess connector
c85 cso30:c:InputProcess connector
c86 cso30:c:OutputProcess connector
p32_propro_p32
PMID: 17349209, 17027520
IκBζ binds both p50 homodimers and p65/p50 dimers.
c87 cso30:c:InputProcess connector
c88 cso30:c:InputProcess connector
c89 cso30:c:OutputProcess connector
p33_propro_p33
PMID: 17349209
TIRAP acts as a bridging adaptor between TLR4, TLR1/2, TLR2/6 and MyD88.
c90 cso30:c:InputProcess connector
c91 cso30:c:InputProcess connector
c92 cso30:c:OutputProcess connector
p34_propro_p34
PMID: 17349209
TIRAP acts as a bridging adaptor between TLR4, TLR1/2, TLR2/6 and MyD88.
c93 cso30:c:InputProcess connector
c94 cso30:c:InputProcess connector
c95 cso30:c:OutputProcess connector
p35_propro_p35
PMID: 17349209
TIRAP acts as a bridging adaptor between TLR4, TLR1/2, TLR2/6 and MyD88.
c96 cso30:c:InputProcess connector
c97 cso30:c:InputProcess connector
c104 cso30:c:OutputProcess connector
p36_propro_p36
PMID: 17349209
TRIF is associated only with TLR4 and TLR3, binding directly to TLR3 and using the bridging adaptor TRAM to bind to TLR4.
c98 cso30:c:InputProcess connector
c99 cso30:c:InputProcess connector
c100 cso30:c:OutputProcess connector
p37_propro_p37
PMID: 17349209
TRIF is associated only with TLR4 and TLR3, binding directly to TLR3 and using the bridging adaptor TRAM to bind to TLR4.
c101 cso30:c:InputProcess connector
c102 cso30:c:InputProcess connector
c103 cso30:c:OutputProcess connector
p38_propro_p38
PMID: 17349209
TRIF is associated only with TLR4 and TLR3, binding directly to TLR3 and using the bridging adaptor TRAM to bind to TLR4.
c105 cso30:c:InputProcess connector
c106 cso30:c:InputProcess connector
c107 cso30:c:OutputProcess connector
p39_propro_p39
PMID: 17349209
TRIF is associated only with TLR4 and TLR3, binding directly to TLR3 and using the bridging adaptor TRAM to bind to TLR4.
c108 cso30:c:InputProcess connector
c109 cso30:c:InputProcess connector
c110 cso30:c:OutputProcess connector
p40_propro_p40
PMID: 17349209
TIRAP acts as a bridging adaptor between TLR4, TLR1/2, TLR2/6 and MyD88.
c111 cso30:c:InputProcess connector
c112 cso30:c:InputProcess connector
c113 cso30:c:OutputProcess connector
p41_propro_p41
PMID: 17349209
TIRAP acts as a bridging adaptor between TLR4, TLR1/2, TLR2/6 and MyD88.
c114 cso30:c:InputProcess connector
c115 cso30:c:InputProcess connector
c116 cso30:c:OutputProcess connector
p42_propro_p42
PMID: 17349209
TIRAP acts as a bridging adaptor between TLR4, TLR1/2, TLR2/6 and MyD88.
c117 cso30:c:InputProcess connector
c118 cso30:c:InputProcess connector
c119 cso30:c:OutputProcess connector
p43_propro_p43
PMID: 17349209
TIRAP acts as a bridging adaptor between TLR4, TLR1/2, TLR2/6 and MyD88.
c120 cso30:c:InputProcess connector
c121 cso30:c:InputProcess connector
c122 cso30:c:OutputProcess connector
p44_propro_p44
PMID: 17349209
TIRAP acts as a bridging adaptor between TLR4, TLR1/2, TLR2/6 and MyD88.
c123 cso30:c:InputProcess connector
c124 cso30:c:InputProcess connector
c125 cso30:c:OutputProcess connector
p45_propro_p45
PMID: 17349209
TIRAP acts as a bridging adaptor between TLR4, TLR1/2, TLR2/6 and MyD88.
c126 cso30:c:InputProcess connector
c127 cso30:c:InputProcess connector
c128 cso30:c:OutputProcess connector
p46_propro_p46
PMID: 17349209
MyD88 interacts with TLRs 7, 8 and 9 via its C-terminal TIR domain and associates with all the other TLRs through the bridging adaptor TIRAP.
c129 cso30:c:InputProcess connector
c131 cso30:c:InputProcess connector
c130 cso30:c:OutputProcess connector
p47_propro_p47
PMID: 17349209
MyD88 interacts with TLRs 7, 8 and 9 via its C-terminal TIR domain and associates with all the other TLRs through the bridging adaptor TIRAP.
c132 cso30:c:InputProcess connector
c133 cso30:c:InputProcess connector
c134 cso30:c:OutputProcess connector
p48_propro_p48
PMID: 17349209
MyD88 interacts with TLRs 7, 8 and 9 via its C-terminal TIR domain and associates with all the other TLRs through the bridging adaptor TIRAP.
c135 cso30:c:InputProcess connector
c137 cso30:c:InputProcess connector
c136 cso30:c:OutputProcess connector
p49_propro_p49
PMID: 17349209
MyD88 interacts with TLRs 7, 8 and 9 via its C-terminal TIR domain and associates with all the other TLRs through the bridging adaptor TIRAP.
c138 cso30:c:InputProcess connector
c139 cso30:c:InputProcess connector
c140 cso30:c:OutputProcess connector
p50_propro_p50
c141 cso30:c:InputProcess connector
c143 cso30:c:InputProcess connector
c142 cso30:c:OutputProcess connector
p51_propro_p51
PMID: 17349209
MyD88 interacts with TLRs 7, 8 and 9 via its C-terminal TIR domain and associates with all the other TLRs through the bridging adaptor TIRAP.
c144 cso30:c:InputProcess connector
c146 cso30:c:InputProcess connector
c145 cso30:c:OutputProcess connector
p52_propro_p52
PMID: 17349209
MyD88 also binds to the kinase IRAK4 through death domains contained in both proteins.
c147 cso30:c:InputProcess connector
c148 cso30:c:InputProcess connector
c149 cso30:c:OutputProcess connector
p53_propro_p53
PMID: 17349209
Receptor associated IRAK4 subsequently phosphorylates IRAK1, which in turn complexes with the E3 ubiquitin ligase TRAF6.
c154 cso30:c:InputProcess connector
c151 cso30:c:OutputProcess connector
p54_propro_p54
PMID: 17349209
This allows the formation of a complex which includes IRAK1, IRAK4 and TRAF6.
c150 cso30:c:InputProcess connector
c152 cso30:c:InputProcess connector
c153 cso30:c:OutputProcess connector
p55_propro_p55
PMID: 17349209
Receptor associated IRAK4 subsequently phosphorylates IRAK1, which in turn complexes with the E3 ubiquitin ligase TRAF6.
c155 cso30:c:InputProcess connector
c156 cso30:c:InputProcess connector
c157 cso30:c:OutputProcess connector
p56_propro_p56
PMID: 17349209, 9261174
Phosphorylated IRAK1 undergoes ubiquitination and proteasomal degradation which most likely serves as a negative feedback loop for TRAF6 activation
c158 cso30:c:InputProcess connector
c159 cso30:c:OutputProcess connector
p57_propro_p57
PMID: 17349209, 9261174
Phosphorylated IRAK1 undergoes ubiquitination and proteasomal degradation which most likely serves as a negative feedback loop for TRAF6 activation
c160 cso30:c:InputProcess connector
c161 cso30:c:OutputProcess connector
c162 cso30:c:OutputProcess connector
p58_propro_p58
PMID: 17349209, 11460167
Activated TRAF6 undergoes K63-mediated polyubiquitination which differs from the K48 form of polyubiquitination in that it does not lead to proteasomal degradation.
PMID: 17349209
The polyubiquitination of TRAF6 appears to be mediated by an E2 complex containing UBC13 and UEV1A.
c163 cso30:c:InputProcess connector
c165 cso30:c:InputAssociation connector
c164 cso30:c:OutputProcess connector
p59_propro_p59
PMID: 17349209
The exact role of TRAF6 polyubiquitination is unclear but it appears to be necessary for the recruitment of TAB1, TAB2 and TAB3.
PMID: 17349209
The N-terminal domain of A20 contains a de-ubiquitinating activity which removes K63-polyubiquitin chains from both RIP1 and TRAF6, thereby inhibiting the recruitment and activation of the TAK1/TAB2/TAB3 complex.
c166 cso30:c:InputProcess connector
c167 cso30:c:InputProcess connector
c168 cso30:c:InputProcess connector
c169 cso30:c:InputProcess connector
c307 cso30:c:InputInhibitor connector
c170 cso30:c:OutputProcess connector
p60_propro_p60
PMID: 17349209, 11460167, 14633987, 14670075
Both TAB2 and TAB3 proteins share the ability to interact with and activate the kinase TAK1.
PMID: 17349209
The N-terminal domain of A20 contains a de-ubiquitinating activity which removes K63-polyubiquitin chains from both RIP1 and TRAF6, thereby inhibiting the recruitment and activation of the TAK1/TAB2/TAB3 complex.
c171 cso30:c:InputProcess connector
c172 cso30:c:InputProcess connector
c308 cso30:c:InputInhibitor connector
c173 cso30:c:OutputProcess connector
p61_propro_p61
PMID: 17349209, 11460167, 14633987, 14670075
Both TAB2 and TAB3 proteins share the ability to interact with and activate the kinase TAK1.
PMID: 17349209
The mechanism of TAK1 activation by recruitment to the TRAF6/TAB2/TAB3 complex is unclear but it may involve a trans-autophosphorylation event induced by dimerisation or oligomerisation.
c174 cso30:c:InputProcess connector
c175 cso30:c:OutputProcess connector
p62_propro_p62
PMID: 17349209, 16186825
In addition to NF-κB activation, TAK1 is also required for the activation of JNK and p38 and subsequent AP-1 activity following TLR stimulation.
c176 cso30:c:InputProcess connector
c178 cso30:c:InputAssociation connector
c177 cso30:c:OutputProcess connector
p63_propro_p63
PMID: 17349209, 16186825
In addition to NF-κB activation, TAK1 is also required for the activation of JNK and p38 and subsequent AP-1 activity following TLR stimulation.
c179 cso30:c:InputProcess connector
c181 cso30:c:InputAssociation connector
c180 cso30:c:OutputProcess connector
p64_propro_p64
PMID: 17349209, 16186825
In addition to NF-κB activation, TAK1 is also required for the activation of JNK and p38 and subsequent AP-1 activity following TLR stimulation.
c182 cso30:c:InputProcess connector
c184 cso30:c:InputAssociation connector
c183 cso30:c:OutputProcess connector
p65_propro_p65
PMID: 17349209
In this case, RIP1 binds to a RIP homotypic interaction motif (RHIM) in TRIF to trigger downstream NF-κB activating events.
c185 cso30:c:InputProcess connector
c186 cso30:c:InputProcess connector
c187 cso30:c:OutputProcess connector
p66_propro_p66
PMID: 17349209
In this case, RIP1 binds to a RIP homotypic interaction motif (RHIM) in TRIF to trigger downstream NF-κB activating events.
c188 cso30:c:InputProcess connector
c189 cso30:c:InputProcess connector
c190 cso30:c:OutputProcess connector
p67_propro_p67
PMID: 17349209, 10755617, 16543241, 16547522
RIP1 has been reported to be K63-polyubiquitinated upon recruitment to the TNFR which facilitates its interaction with IKKγ via a C-terminal ubiquitin binding domain in IKKγ
c191 cso30:c:InputProcess connector
c192 cso30:c:InputProcess connector
c193 cso30:c:OutputProcess connector
p68_propro_p68
PMID: 17349209, 10755617, 16543241, 16547522
RIP1 has been reported to be K63-polyubiquitinated upon recruitment to the TNFR which facilitates its interaction with IKKγ via a C-terminal ubiquitin binding domain in IKKγ
c194 cso30:c:InputProcess connector
c195 cso30:c:OutputProcess connector
p69_propro_p69
PMID: 17349209, 10755617, 16543241, 16547522
RIP1 has been reported to be K63-polyubiquitinated upon recruitment to the TNFR which facilitates its interaction with IKKγ via a C-terminal ubiquitin binding domain in IKKγ
c196 cso30:c:InputProcess connector
c197 cso30:c:InputProcess connector
c198 cso30:c:OutputProcess connector
p71_propro_p71
PMID: 17349209, 12471095
TLR3 instead exclusively uses the adaptor protein TRIF which binds directly to the receptor upon activation and is critical in the activation of NF-κB and the induction of interferon-β expression through activation of IRF3.
c202 cso30:c:InputProcess connector
c204 cso30:c:InputAssociation connector
c203 cso30:c:OutputProcess connector
p72_propro_p72
PMID: 17349209, 12471095
TLR3 instead exclusively uses the adaptor protein TRIF which binds directly to the receptor upon activation and is critical in the activation of NF-κB and the induction of interferon-β expression through activation of IRF3.
c317 cso30:c:InputAssociation connector
c206 cso30:c:OutputProcess connector
p74_propro_p74
PMID: 17349209, 9150141, 11931769
Phosphorylation of S276 in the Rel homology domain of p65 by protein kinase A is an important regulatory event which occurs during TLR4 signaling.
c210 cso30:c:InputProcess connector
c212 cso30:c:InputAssociation connector
c211 cso30:c:OutputProcess connector
p73_propro_p73
PMID: 17349209, 9150141, 11931769
Phosphorylation of S276 in the Rel homology domain of p65 by protein kinase A is an important regulatory event which occurs during TLR4 signaling.
c207 cso30:c:InputProcess connector
c209 cso30:c:InputAssociation connector
c208 cso30:c:OutputProcess connector
p75_propro_p75
PMID: 17349209, 8246997, 8437855
In addition, S276 phosphorylation enhances the binding of the transcriptional enhancers CBP and p300 to p65, leading to effective removal of repressive histone deacetylase complexes from target genes
c213 cso30:c:InputProcess connector
c215 cso30:c:InputProcess connector
c214 cso30:c:OutputProcess connector
p76_propro_p76
PMID: 17349209, 8246997, 8437855
In addition, S276 phosphorylation enhances the binding of the transcriptional enhancers CBP and p300 to p65, leading to effective removal of repressive histone deacetylase complexes from target genes
c216 cso30:c:InputProcess connector
c217 cso30:c:InputProcess connector
c218 cso30:c:OutputProcess connector
p77_propro_p77
PMID: 17349209, 12759443
IKKβ has been identified as the key kinase in the TLR4-induced phosphorylation of p65 on S536.
c219 cso30:c:InputProcess connector
c221 cso30:c:InputAssociation connector
c220 cso30:c:OutputProcess connector
p78_propro_p78
PMID: 17349209, 12456660
Three primary acetylation sites have been identified in p65, i.e., K218, K221 and K310, each of which has a distinct modulatory effect on the transcriptional activities of NF-κB
c222 cso30:c:InputProcess connector
c223 cso30:c:OutputProcess connector
p79_propro_p79
PMID: 17349209, 11533489
Acetylation of p65 on K218 and K221 significantly reduces its ability to interact with IκBα, thereby extending the duration of the NF-κB response in the nucleus by preventing the nuclear export of NF-κB/IκBα complexes
c224 cso30:c:InputProcess connector
c227 cso30:c:InputProcess connector
c229 cso30:c:InputInhibitor connector
c228 cso30:c:OutputProcess connector
p80_propro_p80
PMID: 17349209, 11739381, 12471036
The p50 subunit of NF-κB is also acetylated, at K431 and K440, which appears to enhance the transcriptional activity and DNA binding activity of modified heterodimers.
c319 cso30:c:InputProcess connector
c226 cso30:c:OutputProcess connector
p81_propro_p81
PMID: 17349209, 11533489
Acetylation of p65 on K218 and K221 significantly reduces its ability to interact with IκBα, thereby extending the duration of the NF-κB response in the nucleus by preventing the nuclear export of NF-κB/IκBα complexes
c230 cso30:c:InputProcess connector
c232 cso30:c:InputInhibitor connector
c231 cso30:c:OutputProcess connector
p82_propro_p82
PMID: 17349209, 8321203, 8798413, 8404856, 8253080, 7935378, 8670842, 9584180, 10899169
NF-κB has been reported to interact with a number of transcription factors, including C/EBP , AP-1, Sp-1, SRF , STAT6 and SEF
c233 cso30:c:InputProcess connector
c245 cso30:c:InputProcess connector
c235 cso30:c:OutputProcess connector
p83_propro_p83
PMID: 17349209, 8321203, 8798413, 8404856, 8253080, 7935378, 8670842, 9584180, 10899169
NF-κB has been reported to interact with a number of transcription factors, including C/EBP , AP-1, Sp-1, SRF , STAT6 and SEF
c238 cso30:c:InputProcess connector
c239 cso30:c:InputProcess connector
c237 cso30:c:OutputProcess connector
p84_propro_p84
PMID: 17349209, 8321203, 8798413, 8404856, 8253080, 7935378, 8670842, 9584180, 10899169
NF-κB has been reported to interact with a number of transcription factors, including C/EBP , AP-1, Sp-1, SRF , STAT6 and SEF
c240 cso30:c:InputProcess connector
c234 cso30:c:InputProcess connector
c241 cso30:c:OutputProcess connector
p85_propro_p85
PMID: 17349209, 8321203, 8798413, 8404856, 8253080, 7935378, 8670842, 9584180, 10899169
NF-κB has been reported to interact with a number of transcription factors, including C/EBP , AP-1, Sp-1, SRF , STAT6 and SEF
c243 cso30:c:InputProcess connector
c236 cso30:c:InputProcess connector
c244 cso30:c:OutputProcess connector
p86_propro_p86
PMID: 17349209, 8321203, 8798413, 8404856, 8253080, 7935378, 8670842, 9584180, 10899169
NF-κB has been reported to interact with a number of transcription factors, including C/EBP , AP-1, Sp-1, SRF , STAT6 and SEF
c246 cso30:c:InputProcess connector
c248 cso30:c:InputProcess connector
c247 cso30:c:OutputProcess connector
p87_propro_p87
PMID: 17349209, 8321203, 8798413, 8404856, 8253080, 7935378, 8670842, 9584180, 10899169
NF-κB has been reported to interact with a number of transcription factors, including C/EBP , AP-1, Sp-1, SRF , STAT6 and SEF
c250 cso30:c:InputProcess connector
c251 cso30:c:InputProcess connector
c249 cso30:c:OutputProcess connector
p88_propro_p88
PMID: 17349209, 16143103
NF-κB has been shown to directly interact with TRIF-activated IRF3 on target promoters.
c242 cso30:c:InputProcess connector
c252 cso30:c:InputProcess connector
c253 cso30:c:OutputProcess connector
p89_propro_p89
PMID: 17349209, 15241416
IκBζ is itself a TLR inducible gene which associates with p50 and is critical for the induction of the pro-inflammatory cytokines IL-6 and IL-12 following TLR stimulation in macrophages.
c255 cso30:c:InputAssociation connector
c254 cso30:c:OutputProcess connector
p90_propro_p90
PMID: 17349209, 15241416
IκBζ is itself a TLR inducible gene which associates with p50 and is critical for the induction of the pro-inflammatory cytokines IL-6 and IL-12 following TLR stimulation in macrophages.
c256 cso30:c:InputAssociation connector
c258 cso30:c:InputAssociation connector
c257 cso30:c:OutputProcess connector
p91_propro_p91
PMID: 17349209, 15241416
IκBζ is itself a TLR inducible gene which associates with p50 and is critical for the induction of the pro-inflammatory cytokines IL-6 and IL-12 following TLR stimulation in macrophages.
c262 cso30:c:InputAssociation connector
c260 cso30:c:OutputProcess connector
p92_propro_p92
PMID: 17349209, 15241416
IκBζ is itself a TLR inducible gene which associates with p50 and is critical for the induction of the pro-inflammatory cytokines IL-6 and IL-12 following TLR stimulation in macrophages.
c261 cso30:c:InputAssociation connector
c263 cso30:c:InputAssociation connector
c259 cso30:c:OutputProcess connector
p93_propro_p93
PMID: 17349209
The de novo synthesis of the IκB proteins in an NF-κB-dependent manner constitutes a negative feedback loop for NF-κB activity.
c264 cso30:c:InputAssociation connector
c265 cso30:c:OutputProcess connector
p94_propro_p94
PMID: 17349209
The de novo synthesis of the IκB proteins in an NF-κB-dependent manner constitutes a negative feedback loop for NF-κB activity.
c266 cso30:c:InputAssociation connector
c267 cso30:c:OutputProcess connector
p95_propro_p95
PMID: 17349209, 15900032
Newly synthesized IκB proteins enter the nucleus via a nuclear localization signal where they bind free NF-κB dimers and translocate to the cytoplasm as an IκB/NF-κB complex using a nuclear export sequence, thereby terminating NF-κB transcriptional activity
c268 cso30:c:InputProcess connector
c269 cso30:c:OutputProcess connector
p96_propro_p96
PMID: 17349209, 15900032
Newly synthesized IκB proteins enter the nucleus via a nuclear localization signal where they bind free NF-κB dimers and translocate to the cytoplasm as an IκB/NF-κB complex using a nuclear export sequence, thereby terminating NF-κB transcriptional activity
c270 cso30:c:InputProcess connector
c271 cso30:c:InputProcess connector
c272 cso30:c:OutputProcess connector
p97_propro_p97
PMID: 17349209, 15900032
Newly synthesized IκB proteins enter the nucleus via a nuclear localization signal where they bind free NF-κB dimers and translocate to the cytoplasm as an IκB/NF-κB complex using a nuclear export sequence, thereby terminating NF-κB transcriptional activity
c273 cso30:c:InputProcess connector
c274 cso30:c:OutputProcess connector
p98_propro_p98
PMID: 17349209, 15226358
The second mechanism of limiting NF-κB activity was initially discovered in studies of IκBα knockout cells and involves the ubiquitin targeted proteasomal degradation of promoter bound NF-κB.
c275 cso30:c:InputProcess connector
c276 cso30:c:OutputProcess connector
p99_propro_p99
PMID: 17349209, 15226358
The second mechanism of limiting NF-κB activity was initially discovered in studies of IκBα knockout cells and involves the ubiquitin targeted proteasomal degradation of promoter bound NF-κB.
c277 cso30:c:InputProcess connector
c278 cso30:c:OutputProcess connector
p100_propro_p100
PMID: 17349209
IKKα phosphorylation of p65 and c-Rel targets them for proteasomal degradation in the nucleus and is a key event in the termination of the NF-κB response to TLR stimulation.
c279 cso30:c:InputProcess connector
c281 cso30:c:InputAssociation connector
c280 cso30:c:OutputProcess connector
p101_propro_p101
PMID: 17349209
IKKα phosphorylation of p65 and c-Rel targets them for proteasomal degradation in the nucleus and is a key event in the termination of the NF-κB response to TLR stimulation.
c282 cso30:c:InputProcess connector
c283 cso30:c:OutputProcess connector
p102_propro_p102
PMID: 17349209
IKKα phosphorylation of p65 and c-Rel targets them for proteasomal degradation in the nucleus and is a key event in the termination of the NF-κB response to TLR stimulation.
c284 cso30:c:InputProcess connector
c286 cso30:c:InputAssociation connector
c285 cso30:c:OutputProcess connector
p103_propro_p103
PMID: 17349209
IKKα phosphorylation of p65 and c-Rel targets them for proteasomal degradation in the nucleus and is a key event in the termination of the NF-κB response to TLR stimulation.
c287 cso30:c:InputProcess connector
c288 cso30:c:OutputProcess connector
p104_propro_p104
PMID: 17349209, 11751856
TOLLIP interacts with TLR2 and TLR4 as well as IRAK1 and interferes with the activation of NF-κB through MyD88-dependent pathways.
c289 cso30:c:InputProcess connector
c291 cso30:c:InputProcess connector
c290 cso30:c:OutputProcess connector
p105_propro_p105
PMID: 17349209, 11751856
TOLLIP interacts with TLR2 and TLR4 as well as IRAK1 and interferes with the activation of NF-κB through MyD88-dependent pathways.
c292 cso30:c:InputProcess connector
c293 cso30:c:InputProcess connector
c294 cso30:c:OutputProcess connector
p106_propro_p106
PMID: 17349209
In addition, a C-terminal ubiquitin ligase domain of A20 mediates the K48-polyubiquitination of RIP1 leading to its proteasomal degradation.
c297 cso30:c:InputAssociation connector
c199 cso30:c:InputProcess connector
c200 cso30:c:OutputProcess connector
p107_propro_p107
PMID: 17349209
In addition, a C-terminal ubiquitin ligase domain of A20 mediates the K48-polyubiquitination of RIP1 leading to its proteasomal degradation.
c201 cso30:c:InputProcess connector
c299 cso30:c:OutputProcess connector
c295 cso30:c:OutputProcess connector
p108_propro_p108
PMID: 17349209, 12471095
TLR3 instead exclusively uses the adaptor protein TRIF which binds directly to the receptor upon activation and is critical in the activation of NF-κB and the induction of interferon-β expression through activation of IRF3.
c300 cso30:c:InputProcess connector
c302 cso30:c:InputAssociation connector
c301 cso30:c:OutputProcess connector
p70_propro_p70
PMID: 17349209
The N-terminal domain of A20 contains a de-ubiquitinating activity which removes K63-polyubiquitin chains from both RIP1 and TRAF6, thereby inhibiting the recruitment and activation of the TAK1/TAB2/TAB3 complex.
c296 cso30:c:InputProcess connector
c303 cso30:c:InputAssociation connector
c298 cso30:c:OutputProcess connector
p109_propro_p109
PMID: 17349209
The N-terminal domain of A20 contains a de-ubiquitinating activity which removes K63-polyubiquitin chains from both RIP1 and TRAF6, thereby inhibiting the recruitment and activation of the TAK1/TAB2/TAB3 complex.
c304 cso30:c:InputProcess connector
c306 cso30:c:InputAssociation connector
c305 cso30:c:OutputProcess connector
p110_propro_p110
PMID: 17349209
The N-terminal domain of A20 contains a de-ubiquitinating activity which removes K63-polyubiquitin chains from both RIP1 and TRAF6, thereby inhibiting the recruitment and activation of the TAK1/TAB2/TAB3 complex.
c309 cso30:c:InputProcess connector
c310 cso30:c:InputProcess connector
c311 cso30:c:InputProcess connector
c312 cso30:c:InputProcess connector
c314 cso30:c:InputInhibitor connector
c313 cso30:c:OutputProcess connector
p2_propro_p2
PMID: 17349209
p50 is generated from limited proteasomal processing of the p105 protein as is p52 from the p100 protein.
c3 cso30:c:InputProcess connector
c4 cso30:c:OutputProcess connector
p15_propro_p15
c38 cso30:c:InputProcess connector
c39 cso30:c:InputProcess connector
c40 cso30:c:OutputProcess connector
p14_propro_p14
c34 cso30:c:InputProcess connector
c35 cso30:c:InputProcess connector
c36 cso30:c:OutputProcess connector
p19_propro_p111
c315 cso30:c:InputProcess connector
c316 cso30:c:OutputProcess connector
p28_propro_p28
PMID: 17349209, 9135156
IκBε only binds c-Rel and p65 complexes.
c75 cso30:c:InputProcess connector
c76 cso30:c:InputProcess connector
c77 cso30:c:OutputProcess connector
p112_propro_p112
c205 cso30:c:InputProcess connector
c318 cso30:c:OutputProcess connector
p105_enti_MO000000199
p105
p50_enti_MO000000200
p50
IKK_enti_MO000000248
IKK
IKK_enti_e5
IKK
IkappaB-NF-kappaB_enti_e6
IkappaB-NF-kappaB
IkappaB{p}-NF-kappaB_enti_e11
IkappaB{p}-NF-kappaB
IkappaB{p}{ub}:NF-kappaB_enti_e12
IkappaB{p}{ub}:NF-kappaB
protein remnants_enti_MO000019479
protein remnants
NF-kappaB_enti_e14
NF-kappaB
NF-kappaB_enti_e13
NF-kappaB
DNA_enti_e15
DNA
DNA:NF-kappaB_enti_e16
DNA:NF-kappaB
gene_enti_e17
gene
IKK-alpha_enti_MO000000210
IKK-alpha
IKK-beta_enti_MO000000211
IKK-beta
IKK-gamma_enti_MO000016599
IKK-gamma
A20_enti_MO000016591
A20
A20:IKK-gamma_enti_e18
A20:IKK-gamma
RIP_enti_MO000000208
RIP
IKK-gamma:RIP_enti_e19
IKK-gamma:RIP
IKK-gamma{p}_enti_e20
IKK-gamma{p}
IKK-gamma{ub}{sumo}:ATM_enti_e24
IKK-gamma{ub}{sumo}:ATM
IKK-gamma{sumo}_enti_e25
Sumo
IKK-gamma{sumo}
IKK-gamma{sumo}_enti_e26
Sumo
IKK-gamma{sumo}
ATM_enti_MO000030934
ATM
IKK-gamma{sumo}:ATM_enti_e27
IKK-gamma{sumo}:ATM
IKK-gamma{ub}{sumo}:ATM_enti_e28
IKK-gamma{ub}{sumo}:ATM
NF-kappaB{active}_enti_e29
NF-kappaB{active}
IkappaB-alpha_enti_MO000000233
IkappaB-alpha
IkappaB-beta_enti_MO000000234
IkappaB-beta
NF-kappaB:c-Rel_enti_e30
NF-kappaB:c-Rel
IkappaB-alpha:C-Rel:NF-kappaB_enti_e31
IkappaB-alpha:C-Rel:NF-kappaB
IkappaB-beta:C-Rel:NF-kappaB_enti_e32
IkappaB-beta:C-Rel:NF-kappaB
p65:NF-kappaB_enti_e33
p65:NF-kappaB
IkappaB-alpha:p65:NF-kappaB_enti_e34
IkappaB-alpha:p65:NF-kappaB
IkappaB-beta:p65:NF-kappaB_enti_e35
IkappaB-beta:p65:NF-kappaB
Bcl-3_enti_MO000000238
Bcl-3
(p50)2_enti_MO000016636
(p50)2
Bcl-3:(p50)2_enti_e38
Bcl-3:(p50)2
Bcl-3:(p52)2_enti_e39
Bcl-3:(p52)2
(p52)2_enti_e40
(p52)2
IkappaB-zeta_enti_e41
IkappaB-zeta
(p50)2:IkappaB-zeta_enti_e42
(p50)2:IkappaB-zeta
p50:p65_enti_e43
p50:p65
p50:p65:IkappaB-zeta_enti_e44
p50:p65:IkappaB-zeta
TLR4_enti_MO000019394
TLR4
LPS_enti_MO000042409
LPS
LPS:TLR4_enti_e7
LPS:TLR4
TIRAP_enti_MO000022528
TIRAP
LPS:TLR4:TIRAP_enti_e8
LPS:TLR4:TIRAP
MyD88_enti_MO000016573
MyD88
LPS:TLR4:TIRAP:MYD88_enti_e45
LPS:TLR4:TIRAP:MYD88
TLR3_enti_MO000019398
TLR3
TLR3 ligand_enti_e46
TLR3 ligand
TLR3 ligand:TLR3_enti_e47
TLR3 ligand:TLR3
TRIF_enti_MO000041125
TRIF
TLR3 ligand: TLR3: TRIF_enti_e48
TLR3 ligand: TLR3: TRIF
TRAM_enti_MO000041132
TRAM
LPS:TLR4:TRAM:TRIF_enti_e49
LPS:TLR4:TRAM:TRIF
LPS:TLR4:TRAM_enti_e63
LPS:TLR4:TRAM
TLR1:TLR2_enti_e64
TLR1:TLR2
TLR2 ligand_enti_e65
TLR2 ligand
TLR2 ligand:TLR1:TLR2_enti_e66
TLR2 ligand:TLR1:TLR2
TLR1:TLR2:TIRAP_enti_e67
TLR1:TLR2:TIRAP
TLR1:TLR2:TIRAP:MYD88_enti_e68
TLR1:TLR2:TIRAP:MYD88
TLR2:TLR6_enti_e69
TLR2:TLR6
TLR2ligand:TLR2:TLR6_enti_e70
TLR2ligand:TLR2:TLR6
TLR2 ligand:TLR2:TLR6:TIRAP_enti_e71
TLR2 ligand:TLR2:TLR6:TIRAP
TLR2 ligand: TLR2:TLR6: TIRAP:MYD88_enti_e72
TLR2 ligand: TLR2:TLR6: TIRAP:MYD88
TLR7_enti_MO000042126
TLR7
TLR7 ligand_enti_e73
TLR7 ligand
TLR7 ligand: TLR7_enti_e74
TLR7 ligand: TLR7
TLR7 ligand:TLR7:MYD88_enti_e75
TLR7 ligand:TLR7:MYD88
TLR8_enti_MO000042007
TLR8
e76_enti_e76
e76
TLR8 ligand_enti_e77
TLR8 ligand
TLR8 ligand:TLR8:MYD88_enti_e78
TLR8 ligand:TLR8:MYD88
TLR9_enti_MO000042012
TLR9
TLR9 ligand: TLR9_enti_e79
TLR9 ligand: TLR9
TLR9 ligand_enti_e80
TLR9 ligand
TLR9 ligand:TLR9:MYD88_enti_e81
TLR9 ligand:TLR9:MYD88
IRAK-4_enti_MO000039077
IRAK-4
LPS:TLR4:TIRAP:MYD88:IRAK-4_enti_e82
LPS:TLR4:TIRAP:MYD88:IRAK-4
IRAK1_enti_e83
IRAK1
LPS:TLR4:TIRAP:MYD88:IRAK-4:IRAK1_enti_e85
LPS:TLR4:TIRAP:MYD88:IRAK-4:IRAK1
LPS:TLR4:TIRAP:MYD88:IRAK-4:IRAK1{p}_enti_e84
LPS:TLR4:TIRAP:MYD88:IRAK-4:IRAK1{p}
TRAF6_enti_MO000000212
TRAF6
LPS:TLR4:TIRAP:MYD88:IRAK-4:IRAK1{p}:TRAF6_enti_e86
LPS:TLR4:TIRAP:MYD88:IRAK-4:IRAK1{p}:TRAF6
LPS:TLR4:TIRAP:MYD88:IRAK-4:IRAK1{p}{ub}:TRAF6_enti_e87
LPS:TLR4:TIRAP:MYD88:IRAK-4:IRAK1{p}{ub}:TRAF6
LPS:TLR4:TIRAP:MYD88:IRAK-4:TRAF6_enti_e88
LPS:TLR4:TIRAP:MYD88:IRAK-4:TRAF6
LPS:TLR4:TIRAP:MYD88:IRAK-4:TRAF6{ub}_enti_e89
LPS:TLR4:TIRAP:MYD88:IRAK-4:TRAF6{ub}
UBC13:Uev1A_enti_e90
UBC13:Uev1A
TAB1_enti_MO000016588
TAB1
TAB2_enti_MO000022125
TAB2
TAB3_enti_MO000041541
TAB3
LPS:TLR4:TIRAP:MYD88:IRAK-4:TRAF6{ub}:TAB1:TAB2:TAB3_enti_e91
LPS:TLR4:TIRAP:MYD88:IRAK-4:TRAF6{ub}:TAB1:TAB2:TAB3
TAK1_enti_MO000016574
TAK1
LPS:TLR4:TIRAP:MYD88:IRAK-4:TRAF6{ub}:TAB1:TAB2:TAB3:TAK1_enti_e92
LPS:TLR4:TIRAP:MYD88:IRAK-4:TRAF6{ub}:TAB1:TAB2:TAB3:TAK1
LPS:TLR4:TIRAP:MYD88:IRAK-4:TRAF6{ub}:TAB1:TAB2:TAB3:TAK1{active}_enti_e93
LPS:TLR4:TIRAP:MYD88:IRAK-4:TRAF6{ub}:TAB1:TAB2:TAB3:TAK1{active}
JNK_enti_MO000000023
JNK
JNK{active}_enti_e94
JNK{active}
p38_enti_MO000000022
p38
p38_enti_e95
p38
AP-1_enti_MO000000276
AP-1
AP-1{active}_enti_e96
AP-1{active}
RIP1_enti_MO000000065
RIP1
TLR3 ligand:TLR3:TRIF RIP1_enti_e97
TLR3 ligand:TLR3:TRIF RIP1
LPS:TLR4:TRAM:TRIF:RIP1_enti_e98
LPS:TLR4:TRAM:TRIF:RIP1
TNF-alpha:TNFR:RIP1_enti_e99
TNF-alpha:TNFR:RIP1
TNF-alpha:TNFR:RIP1{ub}_enti_e100
TNF-alpha:TNFR:RIP1{ub}
TNF-alpha:TNFR:RIP1{ub}:IKK-gamma_enti_e101
TNF-alpha:TNFR:RIP1{ub}:IKK-gamma
IRF-3_enti_MO000007694
IRF-3
IRF-3{active}_enti_e103
IRF-3{active}
IFN-beta_enti_G010228
IFN-beta
PKA{active}_enti_e105
PKA{active}
PKA_enti_e106
PKA
RelA-p65{p}_enti_e104
RelA-p65{p}
RelA-p65_enti_MO000000193
RelA-p65
RelA-p65{p}:p300_enti_e107
RelA-p65{p}:p300
p300_enti_MO000019984
p300
CBP_enti_MO000017462
CBP
RelA-p65:CBP_enti_e108
RelA-p65:CBP
RelA-p65{ace}_enti_e109
Ace
RelA-p65{ace}
p50{ace}_enti_e111
Ace
p50{ace}
IkappaB-alpha_enti_e112
IkappaB-alpha
IkappaB-alpha:p65_enti_e113
IkappaB-alpha:p65
IkappaB-alpha:p65_enti_e114
IkappaB-alpha:p65
AP-1{active}_enti_e116
AP-1{active}
NF-kappaB:AP1_enti_e117
NF-kappaB:AP1
c/ebp:F-kappaB_enti_e118
c/ebp:F-kappaB
C/EBP_enti_MO000019416
C/EBP
SP1_enti_e119
SP1
NF-kappaB:SP1_enti_e120
NF-kappaB:SP1
SRF_enti_MO000000059
SRF
NF-kappaB:SRF_enti_e121
NF-kappaB:SRF
NF-kappaB:STAT6_enti_e122
NF-kappaB:STAT6
STAT6_enti_MO000013130
STAT6
NF-kappaB:SEF_enti_e123
NF-kappaB:SEF
SEF_enti_e124
SEF
IRF-3{active}_enti_e115
IRF-3{active}
NF-kappaB:DNA:IRF3_enti_e125
NF-kappaB:DNA:IRF3
IL-6_enti_G010262
IL-6
IL-6_enti_MO000007384
IL-6
IL-12_enti_MO000017265
IL-12
IL-12_enti_e126
IL-12
IkappaB_enti_e127
IkappaB
IkappaB_enti_e128
IkappaB
IkappaB_enti_e129
IkappaB
NF-kappaB:IkappaB_enti_e130
NF-kappaB:IkappaB
DNA:NF-kappaB{ub}_enti_e132
DNA:NF-kappaB{ub}
protein remnants_enti_e133
protein remnants
c-Rel_enti_MO000000192
c-Rel
c-Rel{p}_enti_e134
c-Rel{p}
LPS:TLR4:Tollip_enti_e135
LPS:TLR4:Tollip
Tollip_enti_MO000019406
Tollip
TLR2 ligand:TLR2:TLR6:Tollip_enti_e136
TLR2 ligand:TLR2:TLR6:Tollip
TLR3:TRIF:RIP1{ub}_enti_e102
TLR3:TRIF:RIP1{ub}
TLR4:TRAM:TRIF_enti_e137
TLR4:TRAM:TRIF
TLR3:TRIF:RIP1{ub}:TAB2:TAB3:TAK1_enti_e138
TLR3:TRIF:RIP1{ub}:TAB2:TAB3:TAK1
p100_enti_MO000000202
p100
p52_enti_MO000000196
p52
IL1:IL1R_enti_e22
IL1:IL1R
TNF-alpha_enti_MO000000289
TNF-alpha
TNFR_enti_MO000000205
TNFR
IL-1_enti_MO000000214
IL-1
IL-1R_enti_e23
IL-1R
TNF-alpha:TNFR_enti_e21
TNF-alpha:TNFR
C-Rel: p65_enti_e36
C-Rel: p65
IkappaB-epsilon:C-Rel:p65_enti_e37
IkappaB-epsilon:C-Rel:p65
IkappaB-epsilon_enti_MO000000237
IkappaB-epsilon