_enti_e7
_enti_e8
_enti_e9
_enti_e1
_enti_e10
_enti_e2
_enti_e3
_enti_e4
_enti_e55
_enti_e59
_enti_e53
_enti_e51
_enti_e50
_enti_e56
_enti_e52
_enti_e54
_enti_e58
_enti_e57
_enti_e61
_enti_e60
_enti_e62
g2_fact_g2
g1_fact_g14
g1_fact_g1
g2_fact_g12
g2_fact_g13
p1_propro_p1
PMID: 18249132, 17217339
IRAK-4 was shown to phosphorylate NADPH oxidase p47phox and contribute to cellular oxidative response in neutrophils.
c1 cso30:c:InputProcess connector
c3 cso30:c:InputAssociation connector
c2 cso30:c:OutputProcess connector
p2_propro_p2
PMID: 18249132
Figure 1
c4 cso30:c:InputProcess connector
c5 cso30:c:InputProcess connector
c6 cso30:c:OutputProcess connector
p3_propro_p3
c7 cso30:c:InputProcess connector
c8 cso30:c:InputProcess connector
c9 cso30:c:OutputProcess connector
p4_propro_p4
PMID: 18249132
From fig.1
c10 cso30:c:InputProcess connector
c12 cso30:c:InputProcess connector
c13 cso30:c:InputProcess connector
c14 cso30:c:InputProcess connector
c60 cso30:c:InputProcess connector
c11 cso30:c:OutputProcess connector
p5_propro_p5
PMID: 18249132
The first step involves the classical pathway causing the activation of IKKα/β complex, which contributes to IκBα phosphorylation and degradation, and subsequent nuclear translocation of p65/RelA.
c15 cso30:c:InputProcess connector
c17 cso30:c:InputAssociation connector
c16 cso30:c:OutputProcess connector
p6_propro_p6
c18 cso30:c:InputProcess connector
c19 cso30:c:OutputProcess connector
c20 cso30:c:OutputProcess connector
p7_propro_p7
PMID: 18249132
The second step involves IKKε/TBK-1 dependent p65/RelA phosphorylation, which is independent of the classical pathway and IκBα degradation.
c21 cso30:c:InputProcess connector
c23 cso30:c:InputAssociation connector
c22 cso30:c:OutputProcess connector
p8_propro_p8
PMID: 18249132
Figure 1
PMID: 18249132
Recent evidence indicates that IRAK-1 contributes to NFκB activation by facilitating p65/RelA phosphorylation, but not the classical pathway leading to IκBα degradation and p65 nuclear translocation
c24 cso30:c:InputProcess connector
c26 cso30:c:InputAssociation connector
c25 cso30:c:OutputProcess connector
p9_propro_p9
PMID: 18249132
The first step involves the classical pathway causing the activation of IKKα/β complex, which contributes to IκBα phosphorylation and degradation, and subsequent nuclear translocation of p65/RelA.
c27 cso30:c:InputProcess connector
c28 cso30:c:OutputProcess connector
p10_propro_p10
PMID: 18249132, 15767370, 15695821
Perhaps one of the major functions of IRAK-1 is to mediate the ligand-stimulated phosphorylation of IRF5/7.
c29 cso30:c:InputProcess connector
c31 cso30:c:InputAssociation connector
c30 cso30:c:OutputProcess connector
p11_propro_p11
PMID: 18249132, 15767370, 15695821
Perhaps one of the major functions of IRAK-1 is to mediate the ligand-stimulated phosphorylation of IRF5/7.
c32 cso30:c:InputProcess connector
c34 cso30:c:InputAssociation connector
c33 cso30:c:OutputProcess connector
p12_propro_p12
PMID: 18249132, 15767370
In contrast, NFκB-mediated gene expressions such as TNFα seem to be un-altered in IRAK-1/ cells upon challenge with agonists for TLR 7/8 as well as TLR9
c35 cso30:c:InputAssociation connector
c36 cso30:c:OutputProcess connector
p13_propro_p13
PMID: 18249132
Consequently, interferon alpha4 gene expression is dramatically decreased in IRAK-1/ cells following the stimulation with TLR7 and TLR9 ligand.
c44 cso30:c:InputAssociation connector
c37 cso30:c:OutputProcess connector
p14_propro_p14
PMID: 18249132
Consequently, interferon alpha4 gene expression is dramatically decreased in IRAK-1/ cells following the stimulation with TLR7 and TLR9 ligand.
c38 cso30:c:InputProcess connector
c43 cso30:c:InputAssociation connector
c39 cso30:c:OutputProcess connector
p15_propro_p15
PMID: 18249132
Consequently, interferon alpha4 gene expression is dramatically decreased in IRAK-1/ cells following the stimulation with TLR7 and TLR9 ligand.
c41 cso30:c:InputProcess connector
c42 cso30:c:InputAssociation connector
c40 cso30:c:OutputProcess connector
p17_propro_p17
PMID: 18249132, 15767370
In contrast, NFκB-mediated gene expressions such as TNFα seem to be un-altered in IRAK-1/ cells upon challenge with agonists for TLR 7/8 as well as TLR9.
c45 cso30:c:InputProcess connector
c53 cso30:c:InputAssociation connector
c50 cso30:c:OutputProcess connector
p18_propro_p18
PMID: 18249132, 15767370
In contrast, NFκB-mediated gene expressions such as TNFα seem to be un-altered in IRAK-1/ cells upon challenge with agonists for TLR 7/8 as well as TLR9.
c46 cso30:c:InputProcess connector
c52 cso30:c:InputAssociation connector
c49 cso30:c:OutputProcess connector
p19_propro_p19
PMID: 18249132, 15767370
In contrast, NFκB-mediated gene expressions such as TNFα seem to be un-altered in IRAK-1/ cells upon challenge with agonists for TLR 7/8 as well as TLR9.
c47 cso30:c:InputProcess connector
c51 cso30:c:InputAssociation connector
c48 cso30:c:OutputProcess connector
p20_propro_p20
PMID: 18249132, 16107720
T cell co-stimulatory molecule CD26 can trigger the association of IRAK-1 with caveolin on antigen presenting monocytes, which is responsible for the subsequent expression of co-stimulatory molecule CD86.
c54 cso30:c:InputProcess connector
c55 cso30:c:InputProcess connector
c57 cso30:c:InputAssociation connector
c56 cso30:c:OutputProcess connector
p21_propro_p21
PMID: 18249132, 16107720
T cell co-stimulatory molecule CD26 can trigger the association of IRAK-1 with caveolin on antigen presenting monocytes, which is responsible for the subsequent expression of co-stimulatory molecule CD86.
c59 cso30:c:InputAssociation connector
c58 cso30:c:OutputProcess connector
p22_propro_p22
PMID: 18249132, 17161373
Upstream kinases such as IRAK-4 may contribute to the initial phosphorylation of IRAK-1 at Threonine 381
c61 cso30:c:InputProcess connector
c62 cso30:c:OutputProcess connector
p23_propro_p23
PMID: 18249132
Following such event, IRAK-1 can be quickly activated and exhibit self-phosphorylation within its Pro/Ser rich region
c63 cso30:c:InputProcess connector
c64 cso30:c:OutputProcess connector
p24_propro_p24
PMID: 18249132
This self-phosphorylation may subject the IRAK-1 molecule to subsequent ubiquitination and proteosome-mediated degradation.
c65 cso30:c:InputProcess connector
c66 cso30:c:OutputProcess connector
p25_propro_p25
PMID: 18249132
This self-phosphorylation may subject the IRAK-1 molecule to subsequent ubiquitination and proteosome-mediated degradation.
c67 cso30:c:InputProcess connector
c68 cso30:c:OutputProcess connector
c69 cso30:c:OutputProcess connector
p26_propro_p26
PMID: 18249132, 16690127, 15465816
IRAK-1 also gets sumoylated following either LPS or Pam3CSK4 challenge.
c70 cso30:c:InputProcess connector
c72 cso30:c:InputProcess connector
c71 cso30:c:OutputProcess connector
p27_propro_p27
PMID: 18249132, 16690127, 15465816
IRAK-1 also gets sumoylated following either LPS or Pam3CSK4 challenge.
PMID: 18249132, 11960013
MyD88 is critically involved in recruiting IRAK-4 into the TLR4 complex
c73 cso30:c:InputProcess connector
c74 cso30:c:InputProcess connector
c75 cso30:c:InputProcess connector
c76 cso30:c:InputProcess connector
c77 cso30:c:OutputProcess connector
p28_propro_p28
PMID: 18249132, 16690127, 15465816
IRAK-1 also gets sumoylated following either LPS or Pam3CSK4 challenge.
c78 cso30:c:InputProcess connector
c79 cso30:c:OutputProcess connector
p29_propro_p29
PMID: 18249132, 15465816
Sumoylated IRAK-1 enters the nucleus and contributes to Stat3 activation and selected gene expression
c80 cso30:c:InputProcess connector
c81 cso30:c:OutputProcess connector
c82 cso30:c:OutputProcess connector
p30_propro_p30
PMID: 18249132, 15465816
Sumoylated IRAK-1 enters the nucleus and contributes to Stat3 activation and selected gene expression
c83 cso30:c:InputProcess connector
c85 cso30:c:InputAssociation connector
c84 cso30:c:OutputProcess connector
p31_propro_p31
PMID: 18249132, 15465816
Sumoylated IRAK-1 enters the nucleus and contributes to Stat3 activation and selected gene expression
c86 cso30:c:InputAssociation connector
c87 cso30:c:OutputProcess connector
p32_propro_p32
PMID: 18249132
Overexpression of IRAK-1c blocks IL-1β induced MAP kinase activation, suggesting that IRAK-1c may serve as a negative regulator of inflammation.
c88 cso30:c:InputProcess connector
c90 cso30:c:InputAssociation connector
c91 cso30:c:InputInhibitor connector
c89 cso30:c:OutputProcess connector
p33_propro_p33
PMID: 18249132
Upon overexpression, IRAK-2 can associate with MyD88 as well as TRAF6, and activate NFκB-dependent reporter gene expression.
c92 cso30:c:InputProcess connector
c93 cso30:c:InputProcess connector
c94 cso30:c:InputProcess connector
c95 cso30:c:InputProcess connector
c116 cso30:c:InputProcess connector
c96 cso30:c:OutputProcess connector
p34_propro_p34
PMID: 18249132
Upon overexpression, IRAK-2 can associate with MyD88 as well as TRAF6, and activate NFκB-dependent reporter gene expression.
PMID: 18249132, 17878161
A recent study further confirmed that indeed IRAK-2 instead of IRAK-1 is primarily involved in TRAF-6 ubiquitination and NFκB activation
c97 cso30:c:InputProcess connector
c99 cso30:c:InputAssociation connector
c98 cso30:c:OutputProcess connector
p35_propro_p35
PMID: 18249132
Upon overexpression, IRAK-2 can associate with MyD88 as well as TRAF6, and activate NFκB-dependent reporter gene expression.
c100 cso30:c:InputAssociation connector
c101 cso30:c:OutputProcess connector
p36_propro_p36
PMID: 18249132, 11544529
IRAK-2, instead of IRAK-1 can also interact with another distinct TLR intracellular adaptor molecule Mal/TIRAP
c102 cso30:c:InputProcess connector
c103 cso30:c:InputProcess connector
c104 cso30:c:InputProcess connector
c105 cso30:c:OutputProcess connector
p37_propro_p37
PMID: 18249132, 17878161
A recent study further confirmed that indeed IRAK-2 instead of IRAK-1 is primarily involved in TRAF-6 ubiquitination and NFκB activation
c106 cso30:c:InputProcess connector
c107 cso30:c:OutputProcess connector
p38_propro_p38
PMID: 18249132
Upon overexpression, IRAK-2a and IRAK-2b can activate, while IRAK-2c and IRAK-2d inhibit NFκB activation.
c110 cso30:c:InputProcess connector
c113 cso30:c:InputAssociation connector
c111 cso30:c:OutputProcess connector
p39_propro_p39
PMID: 18249132
Upon overexpression, IRAK-2a and IRAK-2b can activate, while IRAK-2c and IRAK-2d inhibit NFκB activation.
c108 cso30:c:InputProcess connector
c112 cso30:c:InputAssociation connector
c114 cso30:c:InputInhibitor connector
c115 cso30:c:InputInhibitor connector
c109 cso30:c:OutputProcess connector
p40_propro_p40
PMID: 18249132
From fig.2
c117 cso30:c:InputProcess connector
c119 cso30:c:InputAssociation connector
c118 cso30:c:OutputProcess connector
p41_propro_p41
PMID: 18249132
From fig.2
c120 cso30:c:InputProcess connector
c122 cso30:c:InputAssociation connector
c121 cso30:c:OutputProcess connector
p16_propro_p16
PMID: 18249132
From fig.2
PMID: 18249132, 17892204
we have observed that IRAK-M primarily affects the alternative NIK-IKKα/IKKα-RelB NFκB pathway, instead of the classical TAK1-IKKα/IKKβ-RelA pathway
c123 cso30:c:InputProcess connector
c125 cso30:c:InputAssociation connector
c129 cso30:c:InputInhibitor connector
c124 cso30:c:OutputProcess connector
p42_propro_p42
PMID: 18249132
From fig.2
c126 cso30:c:InputProcess connector
c128 cso30:c:InputAssociation connector
c127 cso30:c:OutputProcess connector
p43_propro_p43
PMID: 18249132
From fig.2
c130 cso30:c:InputAssociation connector
c131 cso30:c:OutputProcess connector
p44_propro_p44
PMID: 18249132
From fig.2
c133 cso30:c:InputAssociation connector
c132 cso30:c:OutputProcess connector
p45_propro_p45
PMID: 18249132
From fig.2
c134 cso30:c:InputProcess connector
c135 cso30:c:OutputProcess connector
p46_propro_p46
PMID: 18249132
From fig.2
c136 cso30:c:InputProcess connector
c137 cso30:c:InputProcess connector
c138 cso30:c:OutputProcess connector
p47_propro_p47
PMID: 18249132
From fig.2
c139 cso30:c:InputProcess connector
c140 cso30:c:OutputProcess connector
p48_propro_p48
PMID: 18249132
From fig.2
c142 cso30:c:InputAssociation connector
c141 cso30:c:OutputProcess connector
p49_propro_p49
PMID: 18249132
Upon TCR stimulation, IRAK-4 is recruited to T cell lipid rafts, where it can associate with Zap70 and activate protein kinase C.
c143 cso30:c:InputProcess connector
c144 cso30:c:InputProcess connector
c146 cso30:c:InputProcess connector
c145 cso30:c:OutputProcess connector
p50_propro_p50
PMID: 18249132
Upon TCR stimulation, IRAK-4 is recruited to T cell lipid rafts, where it can associate with Zap70 and activate protein kinase C.
c147 cso30:c:InputProcess connector
c149 cso30:c:InputAssociation connector
c148 cso30:c:OutputProcess connector
p51_propro_p51
PMID: 18249132, 16574867
IRAK-4 is also critically involved in T cell receptor (TCR)-induced T cell proliferation through NFκB activation
c150 cso30:c:InputProcess connector
c152 cso30:c:InputAssociation connector
c151 cso30:c:OutputProcess connector
p52_propro_p52
PMID: 18249132, 16574867
IRAK-4 is also critically involved in T cell receptor (TCR)-induced T cell proliferation through NFκB activation
c153 cso30:c:InputAssociation connector
P47phox_enti_e5
P47phox
p47phox{p}_enti_e6
p47phox{p}
TLR ligand:TLR_enti_e12
TLR ligand:TLR
TLR_enti_e13
TLR
TLR ligand_enti_e14
TLR ligand
MYD88_enti_e15
MYD88
TLR ligand:TLR:MYD88_enti_e16
TLR ligand:TLR:MYD88
IRAK-1_enti_e17
IRAK-1
Tollip_enti_e18
Tollip
TRAF_enti_e19
TRAF
TLR ligand:TLR:MYD88:IRAK-1:TRAF:Tollip:IRAK4_enti_e20
TLR ligand:TLR:MYD88:IRAK-1:TRAF:Tollip:IRAK4
IkappaB-alpha:p50:p65_enti_e21
IkappaB-alpha:p50:p65
IkappaB-alpha:p50:p65_enti_e22
IkappaB-alpha:p50:p65
IKK complex_enti_e23
IKK complex
protein remnants_enti_e24
p50:p65_enti_e25
p50:p65
p50:p65{p}_enti_e26
p50:p65{p}
IKK-epsilon_enti_e27
IKK-epsilon
IKK-epsilon_enti_e28
IKK-epsilon
p50:p65{p}_enti_e29
p50:p65{p}
IRF-5_enti_e30
IRF-5
IRF-5{p}_enti_e31
IRF-5{p}
IRF-7{p}_enti_e32
IRF-7{p}
IRF-7_enti_e33
IRF-7
TNF-alpha_enti_e34
TNF-alpha
IFNA4_enti_e36
IFNA4
IRAK-1{active}_enti_e37
IRAK-1{active}
TLR7 ligand_enti_e38
TLR7 ligand
TLR9 ligand_enti_e39
TLR9 ligand
TLR8 ligand_enti_e40
TLR8 ligand
NF-kappaB_enti_e41
NF-kappaB
NF-kappaB{active}_enti_e42
NF-kappaB{active}
caveolin_enti_e43
caveolin
IRAK-1:caveolin_enti_e44
IRAK-1:caveolin
CD26_enti_e45
CD26
CD86_enti_e46
CD86
IRAK-4_enti_e47
IRAK-4
TLR ligand:TLR:MYD88:IRAK-1{p}:TRAF:Tollip:IRAK4_enti_e48
TLR ligand:TLR:MYD88:IRAK-1{p}:TRAF:Tollip:IRAK4
TLR ligand:TLR:MYD88:TRAF:Tollip:IRAK4_enti_e49
TLR ligand:TLR:MYD88:TRAF:Tollip:IRAK4
TLR ligand:TLR:MYD88:IRAK-1{p}:TRAF:Tollip:IRAK4_enti_e63
TLR ligand:TLR:MYD88:IRAK-1{p}:TRAF:Tollip:IRAK4
TLR ligand:TLR:MYD88:IRAK-1{p}{ub}:TRAF:Tollip:IRAK4_enti_e64
TLR ligand:TLR:MYD88:IRAK-1{p}{ub}:TRAF:Tollip:IRAK4
LPS:TLR4_enti_e65
LPS:TLR4
TLR4_enti_e66
TLR4
LPS_enti_e67
LPS
LPS:TLR4:MYD88:IRAK4:IRAK1_enti_e68
LPS:TLR4:MYD88:IRAK4:IRAK1
LPS:TLR4:MYD88:IRAK4:IRAK1_enti_e69
LPS:TLR4:MYD88:IRAK4:IRAK1
IRAK-1{sumo}_enti_e70
Sumo
IRAK-1{sumo}
LPS:TLR4:MYD88:IRAK4_enti_e71
LPS:TLR4:MYD88:IRAK4
Stat3_enti_e72
Stat3
Stat3{active}_enti_e73
Stat3{active}
gene_enti_e74
gene
IL-1beta_enti_e75
IL-1beta
MAPK_enti_e76
MAPK
MAPK{active}_enti_e77
MAPK{active}
IRAK-1c_enti_e78
IRAK-1c
IRAK-2_enti_e79
IRAK-2
TRAF6_enti_e80
TRAF6
TLR ligand:TLR:MYD88:IRAK-2:TRAF6:IRAK4_enti_e81
TLR ligand:TLR:MYD88:IRAK-2:TRAF6:IRAK4
Mal_enti_e82
Mal
TLR ligand:TLR:MAL:IRAK2_enti_e83
TLR ligand:TLR:MAL:IRAK2
TLR ligand:TLR:MYD88:IRAK-2:TRAF6{ub}:IRAK4_enti_e84
TLR ligand:TLR:MYD88:IRAK-2:TRAF6{ub}:IRAK4
IRAK-2a_enti_e85
IRAK-2a
IRAK-2b_enti_e86
IRAK-2b
IRAK-2c_enti_e87
IRAK-2c
IRAK-2d_enti_e88
IRAK-2d
TAK1_enti_e11
TAK1
TAK1{active}_enti_e89
TAK1{active}
IKK complex_enti_e90
IKK complex
NIK_enti_e91
NIK
NIK{active}_enti_e92
NIK{active}
IRAK-M_enti_e93
IRAK-M
IkappaB-alpha_enti_e94
IkappaB-alpha
IkappaB-alpha_enti_e95
IkappaB-alpha
IkappaB-alpha_enti_e96
IkappaB-alpha
IkappaB-alpha:p50:p65_enti_e97
IkappaB-alpha:p50:p65
inflammatory mediators_enti_e98
inflammatory mediators
TCR ligand:TCR_enti_e99
TCR ligand:TCR
TCR ligand:TCR:Zap-70:IRAK-4_enti_e100
TCR ligand:TCR:Zap-70:IRAK-4
Zap-70_enti_e101
Zap-70
PKC{active}_enti_e102
PKC{active}
PKC_enti_e103
PKC