64646
Pathway
TNF/Stress Related Signaling
Tumour necrosis factor alpha (TNF-a) is a cytokine that activates TNF rector 1 (TNFR1) signalling complex. TNFR1 mediates cell death signalling and inflammation in response to cytokines, bacteria and cellular stress. The classical NFkB pathway involves activation of TNF receptor associated factor 2, receptor interacting serine/threonine protein kinase and death domains which activate the IKK complex, phosphorylating the IKB proteins triggering their degradation resulting in NF-kB dimers dissociation and release. Caspase 2 interacts with TNF-receptor associated factor 2 and receptor interacting serine/threonine protein kinase to activate NFkB. Mitogen activated protein kinases of the MAP3K family are also involved in TNFR1-mediated IKK activation. Mitogen activated kinases can phosphorylate IKK to activate it as well. Activation of Mitogen-activated protein kinase 8 and 14 are involved in the cross-talk of other inflammatory pathways.
Protein
PW064784
Center
PathwayVisualizationContext65060
1730
2030
#000099
PathwayVisualization64530
64646
TNF/Stress Related Signaling
Tumour necrosis factor alpha (TNF-a) is a cytokine that activates TNF rector 1 (TNFR1) signalling complex. TNFR1 mediates cell death signalling and inflammation in response to cytokines, bacteria and cellular stress. The classical NFkB pathway involves activation of TNF receptor associated factor 2, receptor interacting serine/threonine protein kinase and death domains which activate the IKK complex, phosphorylating the IKB proteins triggering their degradation resulting in NF-kB dimers dissociation and release. Caspase 2 interacts with TNF-receptor associated factor 2 and receptor interacting serine/threonine protein kinase to activate NFkB. Mitogen activated protein kinases of the MAP3K family are also involved in TNFR1-mediated IKK activation. Mitogen activated kinases can phosphorylate IKK to activate it as well. Activation of Mitogen-activated protein kinase 8 and 14 are involved in the cross-talk of other inflammatory pathways.
Protein
1
229930
https://cgap.nci.nih.gov/Pathways/BioCarta/h_stressPathway
64646
Pathway
229931
29382797
Proudfoot A, Bayliffe A, O'Kane CM, Wright T, Serone A, Bareille PJ, Brown V, Hamid UI, Chen Y, Wilson R, Cordy J, Morley P, de Wildt R, Elborn S, Hind M, Chilvers ER, Griffiths M, Summers C, McAuley DF: Novel anti-tumour necrosis factor receptor-1 (TNFR1) domain antibody prevents pulmonary inflammation in experimental acute lung injury. Thorax. 2018 Aug;73(8):723-730. doi: 10.1136/thoraxjnl-2017-210305. Epub 2018 Jan 29.
64646
Pathway
229932
21232017
Wajant H, Scheurich P: TNFR1-induced activation of the classical NF-kappaB pathway. FEBS J. 2011 Apr;278(6):862-76. doi: 10.1111/j.1742-4658.2011.08015.x. Epub 2011 Feb 8.
64646
Pathway
229933
11994493
Waetzig GH, Seegert D, Rosenstiel P, Nikolaus S, Schreiber S: p38 mitogen-activated protein kinase is activated and linked to TNF-alpha signaling in inflammatory bowel disease. J Immunol. 2002 May 15;168(10):5342-51.
64646
Pathway
229934
15590671
Lamkanfi M, D'hondt K, Vande Walle L, van Gurp M, Denecker G, Demeulemeester J, Kalai M, Declercq W, Saelens X, Vandenabeele P: A novel caspase-2 complex containing TRAF2 and RIP1. J Biol Chem. 2005 Feb 25;280(8):6923-32. doi: 10.1074/jbc.M411180200. Epub 2004 Dec 8.
64646
Pathway
1
Cell
CL:0000000
2
Platelet
CL:0000233
5
Hepatocyte
CL:0000182
3
Neuron
CL:0000540
4
Cardiomyocyte
CL:0000746
7
Epithelial Cell
CL:0000066
1
Homo sapiens
9606
Eukaryote
Human
3
Escherichia coli
562
Prokaryote
12
Mus musculus
10090
Eukaryote
Mouse
24
Solanum lycopersicum
4081
Eukaryote
Tomato
4
Arabidopsis thaliana
3702
Eukaryote
Thale cress
18
Saccharomyces cerevisiae
4932
Eukaryote
Yeast
21
Xenopus laevis
8355
Eukaryote
African clawed frog
6
Caenorhabditis elegans
6239
Eukaryote
Roundworm
49
Bathymodiolus platifrons
220390
Eukaryote
Deep sea mussel
60
Nitzschia sp.
0001
Eukaryote
Nitzschia4
2
Bacteria
2
Prokaryote
Bacteria
17
Rattus norvegicus
10116
Eukaryote
Rat
5
Bos taurus
9913
Eukaryote
Cattle
10
Drosophila melanogaster
7227
Eukaryote
Fruit fly
19
Schizosaccharomyces pombe
4896
Eukaryote
29
Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
559292
Eukaryote
Baker's yeast
25
Escherichia coli (strain K12)
83333
Prokaryote
23
Pseudomonas aeruginosa
287
Prokaryote
5
Cytoplasm
GO:0005737
3
Mitochondrial Matrix
GO:0005759
1
Cytosol
GO:0005829
4
Peroxisome
GO:0005777
13
Endoplasmic Reticulum
GO:0005783
14
Mitochondrial Outer Membrane
GO:0005741
2
Mitochondrion
GO:0005739
7
Endoplasmic Reticulum Membrane
GO:0005789
25
Golgi apparatus
GO:0005794
10
Cell Membrane
GO:0005886
27
Peroxisome Membrane
GO:0005778
15
Nucleus
GO:0005634
26
Golgi apparatus membrane
GO:0000139
35
Chloroplast
GO:0009507
11
Extracellular Space
GO:0005615
12
Mitochondrial Inner Membrane
GO:0005743
19
sarcoplasmic reticulum
GO:0016529
31
Periplasmic Space
GO:0005620
34
Plant-Type Vacuole
GO:0000325
32
Inner Membrane
GO:0070258
36
Membrane
GO:0016020
2
Endothelium
BTO:0000393
1
Liver
BTO:0000759
72
9
7
Nervous System
BTO:0001484
5
cardiocyte
BTO:0001539
8
Blood Vessel
BTO:0001102
74
11
25
Intestine
BTO:0000648
8
5
1
1
PW_BS000008
4
3
1
1
PW_BS000004
16
2
1
2
PW_BS000016
2
1
1
1
PW_BS000002
26
1
1
1
5
PW_BS000026
5
4
1
1
PW_BS000005
18
13
1
1
PW_BS000018
22
14
1
1
PW_BS000022
39
7
1
1
3
PW_BS000039
3
2
1
1
PW_BS000003
21
5
1
1
4
PW_BS000021
46
1
1
4
PW_BS000046
49
7
1
1
PW_BS000049
43
25
1
1
PW_BS000043
14
10
1
PW_BS000014
10
1
7
1
1
PW_BS000010
59
27
1
1
PW_BS000059
23
15
1
1
PW_BS000023
29
1
1
1
PW_BS000029
7
1
1
PW_BS000007
31
1
5
1
1
PW_BS000031
91
8
5
1
1
PW_BS000091
54
1
3
1
5
PW_BS000054
56
26
1
1
PW_BS000056
104
14
3
1
PW_BS000104
111
5
12
1
PW_BS000111
112
2
12
1
PW_BS000112
103
3
3
1
PW_BS000103
147
1
24
1
PW_BS000147
151
1
4
1
PW_BS000151
155
3
24
1
PW_BS000155
161
3
18
1
PW_BS000161
166
1
1
PW_BS000166
178
3
21
1
PW_BS000178
164
4
PW_BS000164
160
1
18
1
PW_BS000160
199
14
18
1
PW_BS000024
205
5
6
1
PW_BS000024
206
2
6
1
PW_BS000024
213
7
18
1
PW_BS000024
211
10
18
PW_BS000024
214
25
18
1
PW_BS000024
216
4
18
1
PW_BS000024
198
5
18
1
PW_BS000024
222
3
4
1
PW_BS000024
132
1
12
1
PW_BS000132
210
13
18
1
PW_BS000024
225
35
4
1
PW_BS000024
249
13
4
1
PW_BS000024
288
14
4
1
PW_BS000024
226
4
4
1
PW_BS000024
290
5
49
1
PW_BS000024
285
10
4
1
PW_BS000024
308
10
1
1
PW_BS000024
133
3
12
1
PW_BS000133
329
14
12
1
PW_BS000028
336
1
12
1
PW_BS000028
334
4
12
1
PW_BS000028
335
27
12
1
PW_BS000028
115
10
12
PW_BS000115
331
7
12
1
PW_BS000028
356
25
12
1
PW_BS000028
130
13
12
1
PW_BS000130
368
3
60
1
PW_BS000028
184
1
2
1
PW_BS000024
372
10
2
PW_BS000028
118
1
17
1
PW_BS000118
135
5
17
1
PW_BS000135
15
11
1
PW_BS000015
253
5
4
1
PW_BS000024
51
8
1
PW_BS000051
383
7
5
1
PW_BS000100
27
15
1
PW_BS000027
223
12
4
1
PW_BS000024
390
7
6
1
PW_BS000112
398
7
17
1
PW_BS000113
406
3
5
1
PW_BS000115
122
5
5
1
PW_BS000122
382
14
5
1
PW_BS000100
407
2
5
1
PW_BS000115
408
4
5
1
PW_BS000115
124
1
5
1
PW_BS000124
429
1
5
1
PW_BS000115
419
25
5
1
PW_BS000115
125
13
5
1
PW_BS000125
405
10
5
PW_BS000115
422
27
5
1
PW_BS000115
120
3
17
1
PW_BS000120
399
14
17
1
PW_BS000113
119
2
17
1
PW_BS000119
374
4
17
1
PW_BS000053
464
1
17
1
PW_BS000115
455
25
17
1
PW_BS000115
136
13
17
1
PW_BS000136
376
10
17
PW_BS000053
375
27
17
1
PW_BS000053
297
5
10
1
PW_BS000024
484
14
10
1
PW_BS000115
479
3
10
1
PW_BS000115
481
2
10
1
PW_BS000115
482
4
10
1
PW_BS000115
299
1
10
1
PW_BS000024
495
7
10
1
PW_BS000115
490
25
10
1
PW_BS000115
478
10
10
PW_BS000115
491
27
10
1
PW_BS000115
300
13
10
1
PW_BS000024
389
14
6
1
PW_BS000112
501
3
6
1
PW_BS000115
502
4
6
1
PW_BS000115
388
1
6
1
PW_BS000112
507
25
6
1
PW_BS000115
209
10
6
PW_BS000024
508
27
6
1
PW_BS000115
395
13
6
1
PW_BS000113
47
19
1
4
PW_BS000047
72
5
1
3
PW_BS000072
61
25
1
7
PW_BS000061
97
1
5
2
1
PW_BS000097
100
5
2
1
PW_BS000100
129
1
5
12
1
PW_BS000129
108
1
3
PW_BS000108
6
1
3
1
PW_BS000006
143
1
5
19
1
PW_BS000143
146
5
19
1
PW_BS000146
107
31
3
PW_BS000107
101
5
3
1
PW_BS000101
117
1
3
1
PW_BS000117
188
1
18
PW_BS000024
212
1
7
18
1
PW_BS000024
163
2
18
1
PW_BS000163
227
34
4
1
PW_BS000024
241
5
29
PW_BS000024
257
15
29
1
PW_BS000024
170
18
PW_BS000170
281
1
25
1
PW_BS000024
17
12
1
1
PW_BS000017
304
1
2
PW_BS000024
315
1
23
PW_BS000024
318
31
23
PW_BS000024
322
1
23
1
PW_BS000024
293
4
1
PW_BS000024
134
12
12
1
PW_BS000134
332
1
7
12
1
PW_BS000028
353
25
12
7
PW_BS000028
384
12
5
1
PW_BS000100
391
12
6
1
PW_BS000112
94
3
PW_BS000094
109
32
3
PW_BS000109
121
12
17
1
PW_BS000121
123
1
7
5
1
PW_BS000123
447
1
7
17
1
PW_BS000115
472
25
17
7
PW_BS000115
298
1
7
10
1
PW_BS000024
513
1
7
6
1
PW_BS000115
228
36
1
PW_BS000024
423
Magnesium
HMDB0000547
Magnesium salts are essential in nutrition, being required for the activity of many enzymes, especially those concerned with oxidative phosphorylation. Physiologically, it exists as an ion in the body. It is a component of both intra- and extracellular fluids and is excreted in the urine and feces. Deficiency causes irritability of the nervous system with tetany, vasodilatation, convulsions, tremors, depression, and psychotic behavior. Magnesium ion in large amounts is an ionic laxative, and magnesium sulfate (Epsom salts) is sometimes used for this purpose. So-called "milk of magnesia" is a water suspension of one of the few insoluble magnesium compounds, magnesium hydroxide; the undissolved particles give rise to its appearance and name. Milk of magnesia is a mild base, and is commonly used as an antacid.
22537-22-0
C00305
888
18420
13-HYDROXY-MAGNESIUM-PROTOPORP
865
DB01378
[Mg++]
Mg
InChI=1S/Mg/q+2
JLVVSXFLKOJNIY-UHFFFAOYSA-N
magnesium(2+) ion
24.305
23.985041898
0
magnesium(2+) ion
2
2
FDB003518
Magnesium;Magnesium ions;Magnesium ion;Magnesium, doubly charged positive ion;Magnesium, ion (mg(2+));Mg(2+);Mg2+
PW_C000423
Mg2+
86
8
227
4
268
16
476
2
727
26
811
5
819
18
883
22
936
39
983
3
992
21
1167
46
1483
49
1529
43
1764
14
2124
10
2411
59
2942
23
3126
29
3373
7
4540
31
4774
91
4869
54
4974
56
5253
104
5329
111
5356
112
5376
103
5906
147
5934
151
6038
155
6094
161
6250
166
6484
178
6594
164
6881
160
6979
199
7170
205
7194
206
7227
213
7233
211
7250
214
7310
216
7313
198
7473
222
11763
132
11843
210
12312
225
12324
249
12513
288
12581
226
12729
290
15275
285
15337
308
77137
133
77236
329
77937
336
78393
334
78417
335
78489
115
78522
331
78536
356
78574
130
80020
368
80045
184
80048
372
80623
118
80654
135
80865
15
80965
253
81841
51
93832
383
94900
27
108596
223
110559
390
115687
398
119974
406
120070
122
120247
382
120702
407
120981
408
121181
124
121265
429
121319
419
121924
125
122086
405
122408
422
122759
120
122921
399
123307
119
123546
374
123835
464
123889
455
124477
136
124637
376
124978
375
125447
297
125598
484
125669
479
125777
481
125921
482
125947
299
125973
495
126000
490
126243
478
126553
491
126753
300
127125
389
127164
501
127380
502
127407
388
127451
507
127804
209
128125
508
128347
395
1104
Phosphate
HMDB0001429
Phosphate is a salt of phosphoric acid. In organic chemistry, a phosphate, or organophosphate, is an ester of phosphoric acid. Organic phosphates are important in biochemistry, biogeochemistry and ecology. Phosphate (Pi) is an essential component of life. In biological systems, phosphorus is found as a free phosphate ion in solution and is called inorganic phosphate, to distinguish it from phosphates bound in various phosphate esters. Inorganic phosphate is generally denoted Pi and at physiological (neutral) pH primarily consists of a mixture of HPO<sup>2-</sup><sub>4</sub> and H<sub>2</sub>PO<sup>-</sup><sub>4</sub> ions. phosphates are most commonly found in the form of adenosine phosphates, (AMP, ADP and ATP) and in DNA and RNA and can be released by the hydrolysis of ATP or ADP. Similar reactions exist for the other nucleoside diphosphates and triphosphates. Phosphoanhydride bonds in ADP and ATP, or other nucleoside diphosphates and triphosphates, contain high amounts of energy which give them their vital role in all living organisms. Phosphate must be actively transported into cells against its electrochemical gradient. In vertebrates, two unrelated families of Na+-dependent Pi transporters carry out this task. Remarkably, the two families transport different Pi species: whereas type II Na+/Pi cotransporters (SCL34) prefer divalent HPO4(2), type III Na+/Pi cotransporters (SLC20) transport monovalent H2PO4. The SCL34 family comprises both electrogenic and electroneutral members that are expressed in various epithelia and other polarized cells. Through regulated activity in apical membranes of the gut and kidney, they maintain body Pi homeostasis, and in salivary and mammary glands, liver, and testes they play a role in modulating the Pi content of luminal fluids. Phosphate levels in the blood play an important role in hormone signaling and in bone homeostasis. In classical endocrine regulation, low serum phosphate induces the renal production of the seco-steroid hormone 1,25-dihydroxyvitamin D3 (1,25(OH)2D3).This active metabolite of vitamin D acts to restore circulating mineral (i.e. phosphate and calcium) levels by increasing absorption in the intestine, reabsorption in the kidney, and mobilization of calcium and phosphate from bone. Thus, chronic renal failure is associated with hyperparathyroidism, which in turn contributes to osteomalacia (softening of the bones). Another complication of chronic renal failure is hyperphosphatemia (low levels of phosphate in the blood). Hyperphosphatemia (excess levels of phosphate in the blood) is a prevalent condition in kidney dialysis patients and is associated with increased risk of mortality. Hypophosphatemia (hungry bone syndrome) has been associated to postoperative electrolyte aberrations and after parathyroidectomy. (PMID: 17581921, 11169009, 11039261, 9159312, 17625581)Fibroblast growth factor 23 (FGF-23) has recently been recognized as a key mediator of phosphate homeostasis, its most notable effect being promotion of phosphate excretion. FGF-23 was discovered to be involved in diseases such as autosomal dominant hypophosphatemic rickets, X-linked hypophosphatemia, and tumor-induced osteomalacia in which phosphate wasting was coupled to inappropriately low levels of 1,25(OH)2D3. FGF-23 is regulated by dietary phosphate in humans. In particular it was found that phosphate restriction decreased FGF-23, and phosphate loading increased FGF-23.
14265-44-2
C00009
1061
18367
CPD-8587
1032
[O-]P([O-])([O-])=O
O4P
InChI=1S/H3O4P/c1-5(2,3)4/h(H3,1,2,3,4)/p-3
NBIIXXVUZAFLBC-UHFFFAOYSA-K
phosphoric acid
94.9714
94.95342
3
phosphoric acid
0
-2
DBMET00532
FDB022617
Nfb orthophosphate;O-phosphoric acid;Ortho-phosphate;Orthophosphate (po43-);Orthophosphate(3-);Phosphate;Phosphate (po43-);Phosphate anion(3-);Phosphate ion (po43-);Phosphate ion(3-);Phosphate trianion;Phosphate(3-);Phosphoric acid ion(3-);Pi;[po4](3-);Orthophosphate;Phosphate ion;Po4(3-);Phosphoric acid;Orthophosphoric acid;Phosphoric acid ion
PW_C001104
Pi
24
4
84
8
814
5
818
18
831
2
980
3
1763
14
1767
49
2500
10
2729
47
2737
46
3129
29
3166
72
3636
61
3851
23
4249
22
4475
31
5031
27
5158
7
5207
97
5216
100
5317
111
5351
112
5381
103
5447
120
5543
129
5573
133
5605
135
5625
108
5693
6
5848
143
5855
146
5911
147
5941
151
6040
155
6100
161
6294
107
6487
178
6691
101
6714
117
6842
188
6889
160
7161
205
7189
206
7212
211
7306
198
7389
210
7402
212
7436
163
7475
222
8196
225
8258
227
10118
241
10134
257
11748
132
11761
115
11773
213
11904
170
11927
164
12014
281
12728
290
13263
223
34819
17
42255
304
42350
315
42435
318
43692
322
77018
253
77194
293
77217
134
77940
336
77966
130
78048
332
78057
329
78245
353
78669
331
80022
368
89279
308
93831
383
94796
384
110558
390
110640
391
113235
94
115845
398
116206
109
119982
406
120069
122
120699
407
121057
124
121216
125
121268
429
121352
121
121409
123
121423
382
121852
405
123304
119
123621
118
123786
136
123838
464
123968
447
123981
399
124405
376
124948
472
125362
479
125446
297
125774
481
125954
299
126221
478
126594
300
126604
298
126723
484
126904
501
127413
388
127783
209
128166
395
128177
513
128315
389
355
NF-κB
ProteinComplex
988
ProteinComplex
PW_EC000355
NF-κB
80072
23
1766
Tumor necrosis factor
P01375
Cytokine that binds to TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. It is mainly secreted by macrophages and can induce cell death of certain tumor cell lines. It is potent pyrogen causing fever by direct action or by stimulation of interleukin-1 secretion and is implicated in the induction of cachexia, Under certain conditions it can stimulate cell proliferation and induce cell differentiation
HMDBP02070
TNF
6p21.3
X01394
1
4244
2
80343
228
80488
8
134406
14
1067
Mitogen-activated protein kinase kinase kinase 1
Q13233
Component of a protein kinase signal transduction cascade. Activates the ERK and JNK kinase pathways by phosphorylation of MAP2K1 and MAP2K4. Activates CHUK and IKBKB, the central protein kinases of the NF-kappa-B pathway
HMDBP01134
MAP3K1
5q11.2
AC008937
1
2.7.11.25
4097
2
80348
228
80357
8
134682
14
1298
Mitogen-activated protein kinase kinase kinase kinase 2
Q12851
Enhances MAP3K1 oligomerization, which may relieve amino-terminal mediated MAP3K1 autoinhibition and lead to activation following autophosphorylation. May play a role in the regulation of vesicle targeting or fusion
HMDBP01394
MAP4K2
11q13
U07349
1
2.7.11.1
80349
228
134683
14
9027
TRAF family member-associated NF-kappa-B activator
Q92844
Adapter protein involved in I-kappa-B-kinase (IKK) regulation which constitutively binds TBK1 and IKBKE playing a role in antiviral innate immunity. Acts as a regulator of TRAF function by maintaining them in a latent state. Blocks TRAF2 binding to LMP1 and inhibits LMP1-mediated NF-kappa-B activation. May control negatively TRAF2-mediated NF-kappa-B activation signaled by CD40, TNFR1 and TNFR2.
TANK
1
80350
228
134684
14
9030
TNF receptor-associated factor 2
Q12933
Regulates activation of NF-kappa-B and JNK and plays a central role in the regulation of cell survival and apoptosis. Required for normal antibody isotype switching from IgM to IgG. Has E3 ubiquitin-protein ligase activity and promotes 'Lys-63'-linked ubiquitination of target proteins, such as BIRC3, RIPK1 and TICAM1. Is an essential constituent of several E3 ubiquitin-protein ligase complexes, where it promotes the ubiquitination of target proteins by bringing them into contact with other E3 ubiquitin ligases. Regulates BIRC2 and BIRC3 protein levels by inhibiting their autoubiquitination and subsequent degradation; this does not depend on the TRAF2 RING-type zinc finger domain. Plays a role in mediating activation of NF-kappa-B by EIF2AK2/PKR. In complex with BIRC2 or BIRC3, promotes ubiquitination of IKBKE.
TRAF2
1
6.3.2.-
80347
228
134685
14
9552
Tumor necrosis factor receptor type 1-associated DEATH domain protein
Q15628
The nuclear form acts as a tumor suppressor by preventing ubiquitination and degradation of isoform p19ARF/ARF of CDKN2A by TRIP12: acts by interacting with TRIP12, leading to disrupt interaction between TRIP12 and isoform p19ARF/ARF of CDKN2A (By similarity). Adapter molecule for TNFRSF1A/TNFR1 that specifically associates with the cytoplasmic domain of activated TNFRSF1A/TNFR1 mediating its interaction with FADD. Overexpression of TRADD leads to two major TNF-induced responses, apoptosis and activation of NF-kappa-B.
TRADD
1
80346
228
80486
8
80492
308
134410
14
4609
Receptor-interacting serine/threonine-protein kinase 1
Q13546
Essential adapter molecule for the activation of NF- kappa-B. Following different upstream signals (binding of inflammatory cytokines, stimulation of pathogen recognition receptors, or DNA damage), particular RIPK1-containing complexes are formed, initiating a limited number of cellular responses. Upon TNFA stimulation RIPK1 is recruited to a TRADD-TRAF complex initiated by TNFR1 trimerization. There, it is ubiquitinated via 'Lys-63'-link chains, inducing its association with the IKK complex, and its activation through NEMO binding of polyubiquitin chains
HMDBP09499
RIPK1
6p25.2
AK304701
1
2.7.11.1
80351
228
80487
8
80493
308
134411
14
9292
Death domain-containing protein CRADD
P78560
Apoptotic adaptor molecule specific for caspase-2 and FASL/TNF receptor-interacting protein RIP. In the presence of RIP and TRADD, CRADD recruits caspase-2 to the TNFR-1 signalling complex.
CRADD
1
80352
228
134686
14
9291
Caspase-2
P42575
Involved in the activation cascade of caspases responsible for apoptosis execution. Might function by either activating some proteins required for cell death or inactivating proteins necessary for cell survival.
CASP2
1
3.4.22.55
80353
228
134687
14
1405
Mitogen-activated protein kinase 14
Q16539
Responds to activation by environmental stress, pro- inflammatory cytokines and lipopolysaccharide (LPS) by phosphorylating a number of transcription factors, such as ELK1 and ATF2 and several downstream kinases, such as MAPKAPK2 and MAPKAPK5. Plays a critical role in the production of some cytokines, for example IL-6. May play a role in stabilization of EPO mRNA during hypoxic stress. Isoform Mxi2 activation is stimulated by mitogens and oxidative stress and only poorly phosphorylates ELK1 and ATF2. Isoform Exip may play a role in the early onset of apoptosis
HMDBP01516
MAPK14
6p21.3-p21.2
AB074150
1
2.7.11.24
4230
2
80354
8
82153
23
1749
Inhibitor of nuclear factor kappa-B kinase subunit alpha
O15111
Acts as part of the IKK complex in the conventional pathway of NF-kappa-B activation and phosphorylates inhibitors of NF-kappa-B thus leading to the dissociation of the inhibitor/NF- kappa-B complex and ultimately the degradation of the inhibitor. As part of the non-canonical pathway of NF-kappa-B activation, the MAP3K14-activated CHUK/IKKA homodimer phosphorylates NFKB2/p100 associated with RelB, inducing its proteolytic processing to NFKB2/p52 and the formation of NF-kappa-B RelB-p52 complexes. Also phosphorylates NCOA3. Phosphorylates 'Ser-10' of histone H3 at NF- kappa-B-regulated promoters during inflammatory responses triggered by cytokines
HMDBP02038
CHUK
10q24-q25
AF080157
1
2.7.11.10
4133
14
80314
8
1222
Inhibitor of nuclear factor kappa-B kinase subunit beta
O14920
Acts as part of the IKK complex in the conventional pathway of NF-kappa-B activation and phosphorylates inhibitors of NF-kappa-B thus leading to the dissociation of the inhibitor/NF- kappa-B complex and ultimately the degradation of the inhibitor. Also phosphorylates NCOA3
HMDBP01302
IKBKB
8p11.2
AF031416
1
2.7.11.10
4134
14
80140
8
8558
NF-kappa-B essential modulator
Q9Y6K9
Regulatory subunit of the IKK core complex which phosphorylates inhibitors of NF-kappa-B thus leading to the dissociation of the inhibitor/NF-kappa-B complex and ultimately the degradation of the inhibitor. Its binding to scaffolding polyubiquitin seems to play a role in IKK activation by multiple signaling receptor pathways. However, the specific type of polyubiquitin recognized upon cell stimulation (either 'Lys-63'-linked or linear polyubiquitin) and its functional importance is reported conflictingly. Also considered to be a mediator for TAX activation of NF-kappa-B. Could be implicated in NF-kappa-B-mediated protection from cytokine toxicity. Essential for viral activation of IRF3. Involved in TLR3- and IFIH1-mediated antiviral innate response; this function requires 'Lys-27'-linked polyubiquitination.
IKBKG
1
80355
8
1808
Nuclear factor NF-kappa-B p105 subunit
P19838
NF-kappa-B is a pleiotropic transcription factor which is present in almost all cell types and is involved in many biological processed such as inflammation, immunity, differentiation, cell growth, tumorigenesis and apoptosis. NF- kappa-B is a homo- or heterodimeric complex formed by the Rel-like domain-containing proteins RELA/p65, RELB, NFKB1/p105, NFKB1/p50, REL and NFKB2/p52 and the heterodimeric p65-p50 complex appears to be most abundant one. The dimers bind at kappa-B sites in the DNA of their target genes and the individual dimers have distinct preferences for different kappa-B sites that they can bind with distinguishable affinity and specificity. Different dimer combinations act as transcriptional activators or repressors, respectively. NF-kappa-B is controlled by various mechanisms of post-translational modification and subcellular compartmentalization as well as by interactions with other cofactors or corepressors. NF-kappa-B complexes are held in the cytoplasm in an inactive state complexed with members of the NF- kappa-B inhibitor (I-kappa-B) family. In a conventional activation pathway, I-kappa-B is phosphorylated by I-kappa-B kinases (IKKs) in response to different activators, subsequently degraded thus liberating the active NF-kappa-B complex which translocates to the nucleus. NF-kappa-B heterodimeric p65-p50 and RelB-p50 complexes are transcriptional activators. The NF-kappa-B p50-p50 homodimer is a transcriptional repressor, but can act as a transcriptional activator when associated with BCL3. NFKB1 appears to have dual functions such as cytoplasmic retention of attached NF-kappa-B proteins by p105 and generation of p50 by a cotranslational processing. The proteasome-mediated process ensures the production of both p50 and p105 and preserves their independent function, although processing of NFKB1/p105 also appears to occur post- translationally. p50 binds to the kappa-B consensus sequence 5'- GGRNNYYCC-3', located in the enhancer region of genes involved in immune response and acute phase reactions. In a complex with MAP3K8, NFKB1/p105 represses MAP3K8-induced MAPK signaling; active MAP3K8 is released by proteasome-dependent degradation of NFKB1/p105
HMDBP02145
NFKB1
4q24
BC051765
1
4145
2
4147
23
80356
8
115939
27
5773
NF-kappa-B inhibitor alpha
P25963
NFKBIA
1
4135
2
4172
23
80142
8
1274
Dual specificity mitogen-activated protein kinase kinase 4
P45985
Dual specificity kinase that activates the JUN kinases MAPK8 (JNK1) and MAPK9 (JNK2) as well as MAPK14 (p38) but not MAPK1 (ERK2) or MAPK3 (ERK1)
HMDBP01366
MAP2K4
17p11.2
CH471108
1
2.7.12.2
4228
2
80358
8
3977
Dual specificity mitogen-activated protein kinase kinase 7
O14733
Stress activated, dual specificity kinase that activates the JUN kinases MAPK8/JNK1, MAPK9/JNK2 and MAPK10/JNK3
HMDBP08761
MAP2K7
19p13.3-p13.2
AF013589
1
2.7.12.2
4098
2
80359
8
80763
23
1424
Mitogen-activated protein kinase 8
P45983
JNK1 isoforms display different binding patterns:beta-1 preferentially binds to c-Jun, whereas alpha-1, alpha-2, and beta- 2 have a similar low level of binding to both c-Jun or ATF2. However, there is no correlation between binding and phosphorylation, which is achieved at about the same efficiency by all isoforms
HMDBP01536
MAPK8
10q11.22
CH471187
1
2.7.11.24
4103
2
80360
8
80764
23
94901
27
134677
166
134700
7
1783
Transcription factor AP-1
P05412
Transcription factor that recognizes and binds to the enhancer heptamer motif 5'-TGA[CG]TCA-3'
HMDBP02090
JUN
1p32-p31
BC006175
1
4109
23
4170
2
80286
8
94902
27
2078
Dual specificity mitogen-activated protein kinase kinase 3
P46734
Dual specificity kinase. Is activated by cytokines and environmental stress in vivo. Catalyzes the concomitant phosphorylation of a threonine and a tyrosine residue in the MAP kinase p38
HMDBP02743
MAP2K3
17q11.2
D87116
1
2.7.12.2
4229
2
80361
8
5771
Dual specificity mitogen-activated protein kinase kinase 6
P52564
MAP2K6
1
2.7.12.2
4117
2
80362
8
3331
Cyclic AMP-dependent transcription factor ATF-1
P18846
This protein binds the cAMP response element (CRE) (consensus:5'-GTGACGT[AC][AG]-3'), a sequence present in many viral and cellular promoters. Binds to the Tax-responsive element (TRE) of HTLV-I. Mediates PKA-induced stimulation of CRE-reporter genes
HMDBP08111
ATF1
12q13
AJ295163
1
80363
8
9601
Tumor necrosis factor receptor superfamily member 1A
P19438
Receptor for TNFSF2/TNF-alpha and homotrimeric TNFSF1/lymphotoxin-alpha. The adapter molecule FADD recruits caspase-8 to the activated receptor. The resulting death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. Contributes to the induction of non-cytocidal TNF effects including anti-viral state and activation of the acid sphingomyelinase.
TNFRSF1A
1
80345
228
80495
308
80598
8
134408
14
1023
Tumor necrosis factor
1
PW_P001023
1167
1766
3
7635
Tumor necrosis factor receptor superfamily, member 1A
1
PW_P007635
15526
1067
15527
1298
15528
9027
15529
9030
15530
9552
15531
4609
15532
9292
15533
9291
1017
Mitogen-activated protein kinase 14
1
PW_P001017
1161
1405
1
421
423
1
2351
I-kappa-B kinase (IKK) complex
1
PW_P002351
5340
1749
1
5341
1222
1
5342
8558
1
7636
NFKB
1
PW_P007636
15534
1808
15535
5773
985
NF-kappa-B inhibitor alpha
1
PW_P000985
1111
5773
1
963
Mitogen-activated protein kinase kinase kinase 1
1
PW_P000963
1089
1067
1
402
423
1
7637
MEK4-MEK7
1
PW_P007637
15536
1274
15537
3977
971
Mitogen-activated protein kinase 8
1
PW_P000971
1097
1424
1
406
423
1
972
Transcription factor AP-1
1
PW_P000972
1098
1783
1
7638
MEK3-MEK6
1
PW_P007638
15538
2078
15539
5771
7639
activating transcription factor 1
1
PW_P007639
15540
3331
433
Activation
PW_I000433
865
1023
ProteinComplex
1
866
7635
ProteinComplex
1
434
Activation
PW_I000434
867
7635
ProteinComplex
1
868
1017
ProteinComplex
1
435
Activation
PW_I000435
869
1017
ProteinComplex
1
870
2351
ProteinComplex
1
437
Activation
PW_I000437
873
2351
ProteinComplex
1
874
7636
ProteinComplex
1
438
Activation
PW_I000438
875
7636
ProteinComplex
1
876
355
ElementCollection
1
439
Activation
PW_I000439
877
7636
ProteinComplex
1
878
985
ProteinComplex
1
440
Activation
PW_I000440
879
963
ProteinComplex
1
880
2351
ProteinComplex
1
442
Activation
PW_I000442
883
963
ProteinComplex
1
884
7637
ProteinComplex
1
443
Activation
PW_I000443
885
7637
ProteinComplex
1
886
971
ProteinComplex
1
444
Activation
PW_I000444
887
971
ProteinComplex
1
888
972
ProteinComplex
1
446
Activation
PW_I000446
891
963
ProteinComplex
1
892
7638
ProteinComplex
1
447
Activation
PW_I000447
893
7638
ProteinComplex
1
894
1017
ProteinComplex
1
448
Activation
PW_I000448
895
1017
ProteinComplex
1
896
7639
ProteinComplex
1
1588637
423
8
9
true
1220
635
10
regular
100
25
1588638
1104
46
false
1310
734
10
regular
44
43
1588639
1104
46
false
1455
734
10
regular
44
43
1588640
1104
46
false
1800
1216
10
regular
44
43
1588641
1104
46
false
1805
1251
10
regular
44
43
1588642
1104
46
false
1358
1190
10
regular
44
43
1588643
1104
46
false
1383
1295
10
regular
44
43
1588644
423
8
9
true
330
375
10
regular
100
25
1588645
1104
46
false
560
1200
10
regular
44
43
1588646
1104
46
false
375
1265
10
regular
44
43
1588647
1104
46
false
300
1195
10
regular
44
43
1588649
423
8
9
true
410
800
10
regular
100
25
1588650
1104
46
false
640
825
10
regular
44
43
1588651
1104
46
false
640
865
10
regular
44
43
1588652
1104
46
false
650
1010
10
regular
44
43
1588653
1104
46
false
650
1040
10
regular
44
43
1588654
423
8
9
true
610
800
10
regular
100
25
1588655
1104
46
false
955
935
10
regular
44
43
1588656
1104
46
false
955
975
10
regular
44
43
9655
355
144
8
false
1380
1380
12
regular
150
70
594955
1766
228
16
false
600
100
8
subunit
regular
170
90
594956
1067
228
2
false
520
465
8
subunit
regular
150
70
594957
1298
228
2
false
520
395
8
subunit
regular
150
70
594958
9027
228
2
false
670
465
8
subunit
regular
150
70
594959
9030
228
2
false
675
395
8
subunit
regular
150
70
594960
9552
228
2
false
815
395
8
subunit
regular
150
70
594961
4609
228
2
false
970
460
8
subunit
regular
150
70
594962
9292
228
2
false
960
395
8
subunit
regular
150
70
594963
9291
228
2
false
820
460
8
subunit
regular
150
70
594964
1405
8
2
false
1370
465
8
subunit
regular
150
70
594965
1749
8
2
false
1310
755
8
subunit
regular
150
70
594966
1222
8
2
false
1445
760
8
subunit
regular
150
70
594967
8558
8
2
false
1375
810
8
subunit
regular
150
70
594969
1808
8
2
false
1380
1185
8
subunit
regular
150
70
594970
5773
8
2
false
1380
1245
8
subunit
regular
150
70
594971
5773
8
2
false
1685
1245
8
subunit
regular
150
70
594972
1067
8
2
false
520
465
8
subunit
regular
150
70
594973
1749
8
2
false
435
1182
8
subunit
regular
150
70
594974
1222
8
2
false
310
1182
8
subunit
regular
150
70
594975
8558
8
2
false
380
1237
8
subunit
regular
150
70
594976
1808
8
2
true
1125
1092
8
subunit
regular
150
70
594977
5773
8
2
true
1125
1152
8
subunit
regular
150
70
594980
1274
8
2
false
520
680
8
subunit
regular
150
70
594981
3977
8
2
false
1305
760
1
subunit
regular
150
70
594982
1424
8
2
false
520
840
8
subunit
regular
150
70
594983
1783
8
2
false
520
1025
8
subunit
regular
150
70
594985
2078
8
2
false
840
785
8
subunit
regular
150
70
594986
5771
8
2
false
835
715
8
subunit
regular
150
70
594987
1405
8
2
false
840
950
8
subunit
regular
150
70
594988
3331
8
2
false
840
1120
8
subunit
regular
150
70
594989
1749
8
2
true
1055
795
8
subunit
regular
150
70
594990
1222
8
2
true
1190
790
1
subunit
regular
150
70
594991
8558
8
2
true
400
585
8
subunit
regular
150
70
594992
9601
80
false
581
280
20
subunit
regular
200
130
482957
1023
64530
228
593533
594955
482958
7635
64530
228
593534
594956
593535
594957
593536
594958
593537
594959
593538
594960
593539
594961
593540
594962
593541
594963
482959
1017
64530
8
593542
594964
8216
1588637
2165981
Cofactor
482960
2351
64530
8
593543
594965
593544
594966
593545
594967
482962
7636
64530
8
593547
594969
593548
594970
482963
985
64530
8
593549
594971
482964
963
64530
8
593550
594972
8217
1588644
2165994
Cofactor
482965
2351
64530
8
593551
594973
593552
594974
593553
594975
482966
7636
64530
8
593554
594976
593555
594977
482969
7637
64530
8
593558
594980
593559
594981
482970
971
64530
8
593560
594982
8219
1588649
2166005
Cofactor
482971
972
64530
8
593561
594983
482973
7638
64530
8
593563
594985
593564
594986
482974
1017
64530
8
593565
594987
8220
1588654
2166014
Cofactor
482975
7639
64530
8
593566
594988
482976
2351
64530
8
593567
594989
593568
594990
593569
594991
2165978
M685 190 C685 220 685 235 685 265
149
false
18
2165979
M686 305 C686 275 685 295 685 265
149
false
18
true
M 25.946855044164835 13.26155629629604 L 11 12 L 17.380887721185843 25.575134323078345
false
2165980
M1120 495 C1186 499 1324 498 1370 500
149
false
18
2165981
M1215 630 L1215 680 L1265 630 z
10
true
18
2165982
M1370 500 C1320 498 1168 499 1120 495
149
false
18
true
M 25.946855044164835 13.26155629629604 L 11 12 L 17.380887721185843 25.575134323078345
false
2165983
M1445 535 C1533 539 1361 485.25 1443 485.25
149
false
1
2165984
M1449 722 C1449 692 1445 565 1445 535
149
false
18
true
M 25.946855044164835 13.26155629629604 L 11 12 L 17.380887721185843 25.575134323078345
false
2165987
M1450 880 C1450 910 1455 1155 1455 1185
149
false
18
2165988
M1455 1185 C1455 1155 1450 910 1450 880
149
false
18
true
M 25.946855044164835 278.261556296296 L 11 277 L 17.380887721185843 290.5751343230783
false
2165989
M1455 1315 C1455 1345 1455 1307.5 1455 1337.5
149
false
18
2165990
M1455 1380 C1455 1350 1455 1367.5 1455 1337.5
149
false
18
true
M 25.946855044164835 13.26155629629604 L 11 12 L 17.380887721185843 25.575134323078345
false
2165991
M1760 1315 C1763 1335 1760 1451 1764 1472
149
false
18
true
M 1361.0644009829866 1155.611518094107 L 1376 1157 L 1369.7346610946918 1143.371150877582
false
2165992
M1530 1280 C1560 1280 1655 1280 1685 1280
149
false
18
2165993
M1685 1280 C1655 1280 1560 1280 1530 1280
149
false
18
true
M 388.94685504416486 13.26155629629604 L 374 12 L 380.38088772118584 25.575134323078345
false
2165994
M325 370 L325 420 L375 370 z
10
true
18
2165995
M595 535 C595 565 595 650 595 680
149
false
18
2165996
M460 1217 C460 1187 458 528 458 498
149
false
18
true
M 25.946855044164835 13.26155629629604 L 11 12 L 17.380887721185843 25.575134323078345
false
2165997
M530 1272 C598 1274 1350 1280 1380 1280
149
false
18
true
M 210.02782028688796 756.132268861112 L 205 742 L 195.27500629660915 753.4203545246638
false
true
M 992.0096189432334 1092.5 L 1005 1085 L 992.0096189432334 1077.5
false
2165998
M1380 1282 C1350 1282 1433 1276 1403 1276
149
false
1
true
M 25.946855044164835 13.26155629629604 L 11 12 L 17.380887721185843 25.575134323078345
false
true
M 292.9903810567666 694.5 L 280 702 L 292.9903810567666 709.5
false
2166002
M595 535 C595 565 595 650 595 680
149
false
18
2166003
M1274 754 C1246 740 853 617 595 535
149
false
18
true
M 25.946855044164835 13.26155629629604 L 11 12 L 17.380887721185843 25.575134323078345
false
2166004
M595 750 C595 780 595 810 595 840
149
false
18
2166005
M405 795 L405 845 L455 795 z
10
true
18
2166006
M595 840 C595 810 595 780 595 750
149
false
18
true
M 25.946855044164835 13.26155629629604 L 11 12 L 17.380887721185843 25.575134323078345
false
2166007
M595 910 C595 940 605 846.25 605 876.25
149
false
1
2166008
M595 1025 C595 995 595 940 595 910
149
false
18
true
M 25.946855044164835 13.26155629629604 L 11 12 L 17.380887721185843 25.575134323078345
false
2166011
M595 535 C595 565 595 650 595 680
149
false
18
2166012
M910 715 C868 689 595 565 595 535
149
false
18
true
M 25.946855044164835 13.26155629629604 L 11 12 L 17.380887721185843 25.575134323078345
false
2166013
M915 855 C915 885 915 920 915 950
149
false
18
2166014
M605 795 L605 845 L655 795 z
10
true
18
2166015
M915 950 C915 920 915 885 915 855
149
false
18
true
M 25.946855044164835 13.26155629629604 L 11 12 L 17.380887721185843 25.575134323078345
false
2166016
M915 1020 C915 1050 915 1090 915 1120
149
false
18
2166017
M915 1120 C915 1090 915 1050 915 1020
149
false
18
true
M 25.946855044164835 13.26155629629604 L 11 12 L 17.380887721185843 25.575134323078345
false
2166018
M520 500 C473 500 513 503 459 501
149
false
18
2166019
M595 680 C595 648 595 565 595 535
149
false
18
true
M 25.946855044164835 13.26155629629604 L 11 12 L 17.380887721185843 25.575134323078345
false
1630
433
64530
228
1667
482957
2165978
Left
1668
482958
2165979
Right
1631
434
64530
8
1669
482958
2165980
Left
1670
482959
2165982
Right
1632
435
64530
8
1671
482959
2165983
Left
1672
482960
2165984
Right
1634
437
64530
8
1675
482960
2165987
Left
1676
482962
2165988
Right
1635
438
64530
8
409
9655
2165990
Right
1677
482962
2165989
Left
1636
439
64530
8
1678
482962
2165992
Left
1679
482963
2165993
Right
1637
440
64530
8
1680
482964
2165995
Left
1681
482965
2165996
Right
1638
437
64530
8
1682
482965
2165997
Left
1683
482966
2165998
Right
1640
442
64530
8
1686
482964
2166002
Left
1687
482969
2166003
Right
1641
443
64530
8
1688
482969
2166004
Left
1689
482970
2166006
Right
1642
444
64530
8
1690
482970
2166007
Left
1691
482971
2166008
Right
1644
446
64530
8
1694
482964
2166011
Left
1695
482973
2166012
Right
1645
447
64530
8
1696
482973
2166013
Left
1697
482974
2166015
Right
1646
448
64530
8
1698
482974
2166016
Left
1699
482975
2166017
Right
1647
440
64530
8
1700
482964
2166018
Left
1701
482976
2166019
Right
883
1588638
884
1588639
885
1588640
886
1588641
887
1588642
888
1588643
889
1588645
890
1588646
891
1588647
892
1588650
893
1588651
894
1588652
895
1588653
896
1588655
897
1588656
63613
2165991
1442
594992
185765
230
1369
1.0
1.0
0
2
14
327
267
220404
M125 447 C125 397 175 347 225 347 C706 347 1332 347 1813 347 C1863 347 1913 397 1913 447 C1913 794 1913 1246 1913 1593 C1913 1643 1863 1693 1813 1693 C1332 1693 706 1693 225 1693 C175 1693 125 1643 125 1593 C125 1246 125 794 125 447
1
true
6
1788.0
1346.0
245412
15
IKB Ubiquitination & Degradation
1638
1460
20
1.3
1.3
160
15
245413
235
Extracellular
1520
206
20
1.3
1.3
200
15
245414
235
Cytoplasm
1530
371
20
1.3
1.3
200
15