101395
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.
Signaling
PW101511
Center
PathwayVisualizationContext101787
2000
2000
#000099
PathwayVisualization101267
101395
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.
Signaling
5
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
421
36
5
PW_BS000115
385
10
5
1
PW_BS000100
410
15
5
1
PW_BS000115
435
15
5
PW_BS000115
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
19650
Tumor necrosis factor
Q27978
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.
TNF
5
131889
421
132991
124
135049
122
19448
Aurora kinase A
Q2TA06
Mitotic serine/threonine kinases that contributes to the regulation of cell cycle progression. Associates with the centrosome and the spindle microtubules during mitosis and plays a critical role in various mitotic events including the establishment of mitotic spindle, centrosome duplication, centrosome separation as well as maturation, chromosomal alignment, spindle assembly checkpoint, and cytokinesis. Required for initial activation of CDK1 at centrosomes. Phosphorylates numerous target proteins, including ARHGEF2, BORA, BRCA1, CDC25B, DLGP5, HDAC6, KIF2A, LATS2, NDEL1, PARD3, PPP1R2, PLK1, RASSF1, TACC3, p53/TP53 and TPX2. Regulates KIF2A tubulin depolymerase activity. Required for normal axon formation. Plays a role in microtubule remodeling during neurite extension. Important for microtubule formation and/or stabilization. Also acts as a key regulatory component of the p53/TP53 pathway, and particularly the checkpoint-response pathways critical for oncogenic transformation of cells, by phosphorylating and stabilizing p53/TP53. Phosphorylates its own inhibitors, the protein phosphatase type 1 (PP1) isoforms, to inhibit their activity (By similarity). Necessary for proper cilia disassembly prior to mitosis (By similarity). Interacts with SIRT2 (By similarity).
AURKA
5
2.7.11.1
131890
421
131902
122
132945
124
20003
Serine/threonine-protein kinase 25
Q6V9V8
Oxidant stress-activated serine/threonine kinase that may play a role in the response to environmental stress. Targets to the Golgi apparatus where it appears to regulate protein transport events, cell adhesion, and polarity complexes important for cell migration (By similarity).
STK25
5
2.7.11.1
131891
421
20006
TRAF family member associated NFKB activator
F6R2Z7
TANK
5
131892
421
20010
TNF receptor-associated factor 6
Q3ZCC3
E3 ubiquitin ligase that, together with UBE2N and UBE2V1, mediates the synthesis of 'Lys-63'-linked-polyubiquitin chains conjugated to proteins, such as IKBKG, IRAK1, AKT1 and AKT2. Also mediates ubiquitination of free/unanchored polyubiquitin chain that leads to MAP3K7 activation. Mediates activation of NF-kappa-B and JUN. May be essential for the formation of functional osteoclasts. Seems to also play a role in dendritic cells (DCs) maturation and/or activation. Represses c-Myb-mediated transactivation, in B-lymphocytes. Adapter protein that seems to play a role in signal transduction initiated via TNF receptor, IL-1 receptor and IL-17 receptor. Regulates osteoclast differentiation by mediating the activation of adapter protein complex 1 (AP-1) and NF-kappa-B, in response to RANK-L stimulation. Together with MAP3K8, mediates CD40 signals that activate ERK in B-cells and macrophages, and thus may play a role in the regulation of immunoglobulin production.
TRAF6
5
2.3.2.27
131893
421
135042
122
135207
385
20011
Tumor necrosis factor receptor type 1-associated DEATH domain protein
Q2KI74
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 (By similarity). 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).
TRADD
5
131894
421
135047
122
20015
Receptor-interacting serine/threonine-protein kinase 2
Q3SZJ2
Serine/threonine/tyrosine kinase that plays an essential role in modulation of innate and adaptive immune responses. Upon stimulation by bacterial peptidoglycans, NOD1 and NOD2 are activated, oligomerize and recruit RIPK2 through CARD-CARD domains. Once recruited, autophosphorylates and undergoes 'Lys-63'-linked polyubiquitination by E3 ubiquitin ligases XIAP, BIRC2 and BIRC3. The polyubiquitinated protein mediates the recruitment of MAP3K7/TAK1 to IKBKG/NEMO and induces 'Lys-63'-linked polyubiquitination of IKBKG/NEMO and subsequent activation of IKBKB/IKKB. In turn, NF-kappa-B is release from NF-kappa-B inhibitors and translocates into the nucleus where it activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. Plays also a role during engagement of the T-cell receptor (TCR) in promoting BCL10 phosphorylation and subsequent NF-kappa-B activation (By similarity).
RIPK2
5
2.7.11.1, 2.7.10.2
131895
421
135048
122
20020
CRADD protein
Q0II52
CRADD
5
131896
421
15041
Caspase-3
Q08DY9
Involved in the activation cascade of caspases responsible for apoptosis execution. At the onset of apoptosis it proteolytically cleaves poly(ADP-ribose) polymerase (PARP) at a '216-Asp-|-Gly-217' bond. Cleaves and activates sterol regulatory element binding proteins (SREBPs) between the basic helix-loop-helix leucine zipper domain and the membrane attachment domain. Cleaves and activates caspase-6, -7 and -9. Involved in the cleavage of huntingtin. Triggers cell adhesion in sympathetic neurons through RET cleavage (By similarity).
CASP3
5
3.4.22.56
120120
124
131897
421
133015
122
135185
385
19458
Mitogen-activated protein kinase 13
Q3T0N5
Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. MAPK13 is one of the four p38 MAPKs which play an important role in the cascades of cellular responses evoked by extracellular stimuli such as proinflammatory cytokines or physical stress leading to direct activation of transcription factors such as ELK1 and ATF2. Accordingly, p38 MAPKs phosphorylate a broad range of proteins and it has been estimated that they may have approximately 200 to 300 substrates each. MAPK13 is one of the less studied p38 MAPK isoforms. Some of the targets are downstream kinases such as MAPKAPK2, which are activated through phosphorylation and further phosphorylate additional targets. Plays a role in the regulation of protein translation by phosphorylating and inactivating EEF2K. Involved in cytoskeletal remodeling through phosphorylation of MAPT and STMN1. Mediates UV irradiation induced up-regulation of the gene expression of CXCL14. Plays an important role in the regulation of epidermal keratinocyte differentiation, apoptosis and skin tumor development. Phosphorylates the transcriptional activator MYB in response to stress which leads to rapid MYB degradation via a proteasome-dependent pathway. MAPK13 also phosphorylates and down-regulates PRKD1 during regulation of insulin secretion in pancreatic beta cells (By similarity).
MAPK13
5
2.7.11.24
131898
122
132946
124
135039
410
135178
435
19503
Inhibitor of nuclear factor kappa-B kinase subunit alpha
A7YWD1
Serine kinase that plays an essential role in the NF-kappa-B signaling pathway which is activated by multiple stimuli such as inflammatory cytokines, bacterial or viral products, DNA damages or other cellular stresses. Acts as part of the canonical IKK complex in the conventional pathway of NF-kappa-B activation and phosphorylates inhibitors of NF-kappa-B on serine residues. These modifications allow polyubiquitination of the inhibitors and subsequent degradation by the proteasome. In turn, free NF-kappa-B is translocated into the nucleus and activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. Negatively regulates the pathway by phosphorylating the scaffold protein TAXBP1 and thus promoting the assembly of the A20/TNFAIP3 ubiquitin-editing complex (composed of A20/TNFAIP3, TAX1BP1, and the E3 ligases ITCH and RNF11). Therefore, CHUK plays a key role in the negative feedback of NF-kappa-B canonical signaling to limit inflammatory gene activation. 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. In turn, these complexes regulate genes encoding molecules involved in B-cell survival and lymphoid organogenesis. Participates also in the negative feedback of the non-canonical NF-kappa-B signaling pathway by phosphorylating and destabilizing MAP3K14/NIK. Within the nucleus, phosphorylates CREBBP and consequently increases both its transcriptional and histone acetyltransferase activities. Modulates chromatin accessibility at NF-kappa-B-responsive promoters by phosphorylating histones H3 at 'Ser-10' that are subsequently acetylated at 'Lys-14' by CREBBP. Additionally, phosphorylates the CREBBP-interacting protein NCOA3. Also phosphorylates FOXO3 and may regulate this pro-apoptotic transcription factor.
CHUK
5
2.7.11.10
131899
122
132953
405
19509
Inhibitor of nuclear factor kappa-B kinase subunit beta
Q95KV0
Serine kinase that plays an essential role in the NF-kappa-B signaling pathway which is activated by multiple stimuli such as inflammatory cytokines, bacterial or viral products, DNA damages or other cellular stresses. Acts as part of the canonical IKK complex in the conventional pathway of NF-kappa-B activation and phosphorylates inhibitors of NF-kappa-B on 2 critical serine residues. These modifications allow polyubiquitination of the inhibitors and subsequent degradation by the proteasome. In turn, free NF-kappa-B is translocated into the nucleus and activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. In addition to the NF-kappa-B inhibitors, phosphorylates several other components of the signaling pathway including NEMO/IKBKG, NF-kappa-B subunits RELA and NFKB1, as well as IKK-related kinases TBK1 and IKBKE. IKK-related kinase phosphorylations may prevent the overproduction of inflammatory mediators since they exert a negative regulation on canonical IKKs. Phosphorylates FOXO3, mediating the TNF-dependent inactivation of this pro-apoptotic transcription factor. Also phosphorylates other substrates including NCOA3, BCL10 and IRS1. Within the nucleus, acts as an adapter protein for NFKBIA degradation in UV-induced NF-kappa-B activation.
IKBKB
5
2.7.11.10
131900
122
132954
405
20023
NF-kappa-B essential modulator
Q5EA16
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. 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 (By similarity).
IKBKG
5
131901
122
19460
Transcription factor AP-1
O77627
Transcription factor that recognizes and binds to the enhancer heptamer motif 5'-TGA[CG]TCA-3'. Promotes activity of NR5A1 when phosphorylated by HIPK3 leading to increased steroidogenic gene expression upon cAMP signaling pathway stimulation. Involved in activated KRAS-mediated transcriptional activation of USP28 in colorectal cancer (CRC) cells. Binds to the USP28 promoter in colorectal cancer (CRC) cells.
JUN
5
131903
122
132947
410
132958
124
135179
435
20026
Cyclic AMP-dependent transcription factor ATF-1
Q08DA8
This protein binds the cAMP response element (CRE) (consensus: 5'-GTGACGT[AC][AG]-3'), a sequence present in many viral and cellular promoters. Mediates PKA-induced stimulation of CRE-reporter genes. Represses the expression of FTH1 and other antioxidant detoxification genes. Triggers cell proliferation and transformation (By similarity).
ATF1
5
131904
122
20031
Tumor necrosis factor receptor superfamily member 1A
Q2HJ72
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 (By similarity).
TNFRSF1A
5
135044
122
10549
Tumor necrosis factor
5
PW_P010549
18987
19650
3
10550
Tumor necrosis factor receptor superfamily, member 1A
5
PW_P010550
18988
19448
18989
20003
18990
20006
18991
20010
18992
20011
18993
20015
18994
20020
18995
15041
10551
Mitogen-activated protein kinase 14
5
PW_P010551
18996
19458
1
10552
I-kappa-B kinase (IKK) complex
5
PW_P010552
18997
19503
1
18998
19509
1
18999
20023
1
10554
Mitogen-activated protein kinase kinase kinase 1
5
PW_P010554
19001
19448
1
10555
Mitogen-activated protein kinase 8
5
PW_P010555
19002
19458
1
10556
Transcription factor AP-1
5
PW_P010556
19003
19460
1
10557
activating transcription factor 1
5
PW_P010557
19004
20026
1129
Activation
PW_I001129
2257
10549
ProteinComplex
1
2258
10550
ProteinComplex
1
1130
Activation
PW_I001130
2259
10550
ProteinComplex
1
2260
10551
ProteinComplex
1
1131
Activation
PW_I001131
2261
10551
ProteinComplex
1
2262
10552
ProteinComplex
1
1132
Activation
PW_I001132
2263
10554
ProteinComplex
1
2264
10552
ProteinComplex
1
1133
Activation
PW_I001133
2265
10555
ProteinComplex
1
2266
10556
ProteinComplex
1
1134
Activation
PW_I001134
2267
10551
ProteinComplex
1
2268
10557
ProteinComplex
1
2419794
423
122
9
true
1100
535
10
regular
100
25
2419795
423
122
9
true
210
275
10
regular
100
25
2419796
423
122
9
true
290
700
10
regular
100
25
2419797
423
122
9
true
490
700
10
regular
100
25
2419798
1104
46
false
1190
634
10
regular
44
43
2419799
1104
46
false
1335
634
10
regular
44
43
2419800
1104
46
false
1680
1116
10
regular
44
43
2419801
1104
46
false
1685
1151
10
regular
44
43
2419802
1104
46
false
1238
1090
10
regular
44
43
2419803
1104
46
false
1263
1195
10
regular
44
43
2419804
1104
46
false
440
1100
10
regular
44
43
2419805
1104
46
false
255
1165
10
regular
44
43
2419806
1104
46
false
180
1095
10
regular
44
43
2419807
1104
46
false
520
725
10
regular
44
43
2419808
1104
46
false
520
765
10
regular
44
43
2419809
1104
46
false
530
910
10
regular
44
43
2419810
1104
46
false
530
940
10
regular
44
43
2419811
1104
46
false
835
835
10
regular
44
43
2419812
1104
46
false
835
875
10
regular
44
43
839872
19650
421
16
false
480
0
8
subunit
regular
170
90
839873
19448
421
2
false
400
365
8
subunit
regular
150
70
839874
20003
421
2
false
400
295
8
subunit
regular
150
70
839875
20006
421
2
false
550
365
8
subunit
regular
150
70
839876
20010
421
2
false
555
295
8
subunit
regular
150
70
839877
20011
421
2
false
695
295
8
subunit
regular
150
70
839878
20015
421
2
false
850
360
8
subunit
regular
150
70
839879
20020
421
2
false
840
295
8
subunit
regular
150
70
839880
15041
421
2
false
700
360
8
subunit
regular
150
70
839881
19458
122
2
false
1250
365
8
subunit
regular
150
70
839882
19503
122
2
false
1190
655
8
subunit
regular
150
70
839883
19509
122
2
false
1325
660
8
subunit
regular
150
70
839884
20023
122
2
false
1255
710
8
subunit
regular
150
70
839885
19448
122
2
false
400
365
8
subunit
regular
150
70
839886
19503
122
2
false
315
1082
8
subunit
regular
150
70
839887
19509
122
2
false
190
1082
8
subunit
regular
150
70
839888
20023
122
2
false
260
1137
8
subunit
regular
150
70
839889
19458
122
2
false
400
740
8
subunit
regular
150
70
839890
19460
122
2
false
400
925
8
subunit
regular
150
70
839891
19458
122
2
false
720
850
8
subunit
regular
150
70
839892
20026
122
2
false
720
1020
8
subunit
regular
150
70
839893
19503
122
2
true
935
695
8
subunit
regular
150
70
839894
19509
122
2
true
1070
690
1
subunit
regular
150
70
839895
20023
122
2
true
280
485
8
subunit
regular
150
70
839896
20031
80
false
461
180
20
subunit
regular
200
130
723726
10549
101267
421
837422
839872
723727
10550
101267
421
837423
839873
837424
839874
837425
839875
837426
839876
837427
839877
837428
839878
837429
839879
837430
839880
723728
10551
101267
122
837431
839881
18633
2419794
3289472
Cofactor
723729
10552
101267
122
837432
839882
837433
839883
837434
839884
723730
10554
101267
122
837435
839885
18634
2419795
3289482
Cofactor
723731
10552
101267
122
837436
839886
837437
839887
837438
839888
723732
10555
101267
122
837439
839889
18635
2419796
3289490
Cofactor
723733
10556
101267
122
837440
839890
723734
10551
101267
122
837441
839891
18636
2419797
3289497
Cofactor
723735
10557
101267
122
837442
839892
723736
10552
101267
122
837443
839893
837444
839894
837445
839895
3269947
M1330 780 C1330 810 1335 1055 1335 1085
149
false
18
3269949
M1335 1085 C1335 1055 1330 810 1330 780
149
false
18
true
M 25.946855044164835 278.261556296296 L 11 277 L 17.380887721185843 290.5751343230783
false
3269950
M1335 1280 C1335 1250 1335 1267.5 1335 1237.5
149
false
18
true
M 25.946855044164835 13.26155629629604 L 11 12 L 17.380887721185843 25.575134323078345
false
3269951
M1335 1215 C1335 1245 1335 1207.5 1335 1237.5
149
false
18
3269953
M1410 1180 C1440 1180 1535 1180 1565 1180
149
false
18
3269954
M1565 1180 C1535 1180 1440 1180 1410 1180
149
false
18
true
M 388.94685504416486 13.26155629629604 L 374 12 L 380.38088772118584 25.575134323078345
false
3269959
M504 1182 C572 1184 1230 1180 1260 1180
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
3269960
M1260 1182 C1230 1182 1313 1176 1283 1176
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
3269961
M475 435 C475 465 475 550 475 580
149
false
18
3269962
M1154 654 C1126 640 733 517 475 435
149
false
18
true
M 25.946855044164835 13.26155629629604 L 11 12 L 17.380887721185843 25.575134323078345
false
3269963
M475 650 C475 680 475 710 475 740
149
false
18
3269965
M475 740 C475 710 475 680 475 650
149
false
18
true
M 25.946855044164835 13.26155629629604 L 11 12 L 17.380887721185843 25.575134323078345
false
3269970
M475 435 C475 465 475 550 475 580
149
false
18
3269971
M790 615 C748 589 475 465 475 435
149
false
18
true
M 25.946855044164835 13.26155629629604 L 11 12 L 17.380887721185843 25.575134323078345
false
3269973
M795 755 C795 785 795 820 795 850
149
false
18
3269976
M795 850 C795 820 795 785 795 755
149
false
18
true
M 25.946855044164835 13.26155629629604 L 11 12 L 17.380887721185843 25.575134323078345
false
3289469
M565 90 C565 120 565 135 565 165
149
false
18
3289470
M566 205 C566 175 565 195 565 165
149
false
18
true
M 25.946855044164835 13.26155629629604 L 11 12 L 17.380887721185843 25.575134323078345
false
3289471
M1000 395 C1066 399 1204 398 1250 400
149
false
18
3289472
M1095 530 L1095 580 L1145 530 z
10
true
18
3289473
M1250 400 C1200 398 1048 399 1000 395
149
false
18
true
M 25.946855044164835 13.26155629629604 L 11 12 L 17.380887721185843 25.575134323078345
false
3289474
M1325 435 C1413 439 1241 385.25 1323 385.25
149
false
1
3289475
M1329 622 C1329 592 1325 465 1325 435
149
false
18
true
M 25.946855044164835 13.26155629629604 L 11 12 L 17.380887721185843 25.575134323078345
false
3289476
M1330 780 C1330 810 1335 1055 1335 1085
149
false
18
3289477
M1335 1085 C1335 1055 1330 810 1330 780
149
false
18
true
M 25.946855044164835 278.261556296296 L 11 277 L 17.380887721185843 290.5751343230783
false
3289478
M1335 1280 C1335 1250 1335 1267.5 1335 1237.5
149
false
18
true
M 25.946855044164835 13.26155629629604 L 11 12 L 17.380887721185843 25.575134323078345
false
3289479
M1335 1215 C1335 1245 1335 1207.5 1335 1237.5
149
false
18
3289480
M1410 1180 C1440 1180 1535 1180 1565 1180
149
false
18
3289481
M1565 1180 C1535 1180 1440 1180 1410 1180
149
false
18
true
M 388.94685504416486 13.26155629629604 L 374 12 L 380.38088772118584 25.575134323078345
false
3289482
M205 270 L205 320 L255 270 z
10
true
18
3289483
M475 435 C475 465 475 550 475 580
149
false
18
3289484
M325 1054 C325 1024 325 428 325 398
149
false
18
true
M 25.946855044164835 13.26155629629604 L 11 12 L 17.380887721185843 25.575134323078345
false
3289485
M504 1182 C572 1184 1230 1180 1260 1180
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
3289486
M1260 1182 C1230 1182 1313 1176 1283 1176
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
3289487
M475 435 C475 465 475 550 475 580
149
false
18
3289488
M1154 654 C1126 640 733 517 475 435
149
false
18
true
M 25.946855044164835 13.26155629629604 L 11 12 L 17.380887721185843 25.575134323078345
false
3289489
M475 650 C475 680 475 710 475 740
149
false
18
3289490
M285 695 L285 745 L335 695 z
10
true
18
3289491
M475 740 C475 710 475 680 475 650
149
false
18
true
M 25.946855044164835 13.26155629629604 L 11 12 L 17.380887721185843 25.575134323078345
false
3289492
M475 810 C475 840 485 746.25 485 776.25
149
false
1
3289493
M475 925 C475 895 475 840 475 810
149
false
18
true
M 25.946855044164835 13.26155629629604 L 11 12 L 17.380887721185843 25.575134323078345
false
3289494
M475 435 C475 465 475 550 475 580
149
false
18
3289495
M790 615 C748 589 475 465 475 435
149
false
18
true
M 25.946855044164835 13.26155629629604 L 11 12 L 17.380887721185843 25.575134323078345
false
3289496
M795 755 C795 785 795 820 795 850
149
false
18
3289497
M485 695 L485 745 L535 695 z
10
true
18
3289498
M795 850 C795 820 795 785 795 755
149
false
18
true
M 25.946855044164835 13.26155629629604 L 11 12 L 17.380887721185843 25.575134323078345
false
3289499
M795 920 C795 950 795 990 795 1020
149
false
18
3289500
M795 1020 C795 990 795 950 795 920
149
false
18
true
M 25.946855044164835 13.26155629629604 L 11 12 L 17.380887721185843 25.575134323078345
false
3289501
M400 400 C334 400 380 402 326 400
149
false
18
3289502
M475 580 C475 548 475 465 475 435
149
false
18
true
M 25.946855044164835 13.26155629629604 L 11 12 L 17.380887721185843 25.575134323078345
false
3289503
M1640 1215 C1643 1235 1640 1351 1644 1372
149
false
18
true
M 1361.0644009829866 1155.611518094107 L 1376 1157 L 1369.7346610946918 1143.371150877582
false
3769
1129
101267
421
4788
723726
3289469
Left
4789
723727
3289470
Right
3770
1130
101267
122
4790
723727
3289471
Left
4791
723728
3289473
Right
3771
1131
101267
122
4792
723728
3289474
Left
4793
723729
3289475
Right
3772
1132
101267
122
4794
723730
3289483
Left
4795
723731
3289484
Right
3773
1133
101267
122
4796
723732
3289492
Left
4797
723733
3289493
Right
3774
1134
101267
122
4798
723734
3289499
Left
4799
723735
3289500
Right
3775
1132
101267
122
4800
723730
3289501
Left
4801
723736
3289502
Right
1912
2419798
1913
2419799
1914
2419800
1915
2419801
1916
2419802
1917
2419803
1918
2419804
1919
2419805
1920
2419806
1921
2419807
1922
2419808
1923
2419809
1924
2419810
1925
2419811
1926
2419812
65622
3289503
2469
839896
334145
M5 347 C5 297 55 247 105 247 C584 247 1206 247 1685 247 C1735 247 1785 297 1785 347 C1785 668 1785 1084 1785 1405 C1785 1455 1735 1505 1685 1505 C1206 1505 584 1505 105 1505 C55 1505 5 1455 5 1405 C5 1084 5 668 5 347
1
true
6
1780.0
1258.0
408800
15
IKB Ubiquitination & Degradation
1518
1360
20
1.3
1.3
160
15
408801
235
Extracellular
1400
106
20
1.3
1.3
200
15
408802
235
Cytoplasm
1410
271
20
1.3
1.3
200
15