70482
Pathway
Toll-Like Receptor Pathway 2
Toll-like receptors (TLRs) are a type of pattern recognition receptor that spans the cell membrane and recognizes conserved microbial molecules. TLRs get their name from the toll gene in Drosophila, which produces a protein that is similar in structure to TLR proteins. Each TLR is able to recognize specific unique molecules associated with pathogens, including lipoproteins, lipopolysaccharides, double stranded RNA, flagellin and others. Recognition of pathogen molecules allows the immune system to detect extracellular pathogens.
TLR2 can form heterodimers on the surface of the cell's plasma membrane with either TLR1 or TLR6. These dimers, along with another protein known as CD14 as a cofactor, can detect different microbial lipoproteins. Following binding of lipoproteins to these complexes, they activate a protein known as myeloid differentiation primary response protein (MyD88). MyD88 then joins with interleukin-1 receptor-associated kinase 1 (IRAK1) to form a complex.
TLR4 is another TLR that detects lipopolysaccharides (LPS) that make up the outer membrane of Gram-negative bacteria. It associates with two other proteins, monocyte differentiation antigen CD14, and lymphocyte antigen 96 (MD2), which allow it to better bind LPS. Once LPS has bound to the complex, it activates signalling to the toll/interleukin-1 receptor domain-containing adaptor protein (TIRAP) and Toll-interacting protein (TOLLIP), which then recruit MyD99 and IRAK1 to the TLR on the cell surface.
Other TLRs have slightly more simple pathways, including TLR9, which recognizes CpG-DNA, which is a section of DNA with a cytosine followed by a guanine and are found commonly in pathogen genomes. TLRs 3 and 8 both recognize double stranded RNA, which is found in some viruses. TLR7 recognizes single stranded RNA from internalized viral genomes, and can also be activated by the drug Imiquimod, sold as Aldara. Imiquimod is used to treat genital warts , actinic keratosis and basal cell carcinoma by activating the immune system in the area it was applied. Finally, TLR5 recognizes the bacterial flagellin proteins. When any of these substances bind their respective TLRs, the TLRs signal to the MyD88 and IRAK1 complex.
After any of these activation mechanisms occurs, the IRAK protein, which is a kinase, phosphorylates and activates TNF receptor-associated factor 6 (TRAF6). TRAF6 then interacts with the evolutionarily conserved signaling intermediate in Toll pathway (ECSIT). ECSIT then activates mitogen-activated protein kinase kinase kinase 1 (MAP3K1). This then phosphorylates the IKK complex, comprised of inhibitors of nuclear factor kappa-B kinase subunits alpha and beta (IKKA and IKKB), as well as its regulatory subunit, NF-kappa-B essential modulator (NEMO).
Another pathway starting with the activation of TRAF6 leads to this same point. First, TRAF6 activates a complex consisting of mitogen-activated protein kinase kinase kinase 7 (MAP3K7), as well as TGF-beta-activated kinase 1 (TAK1) and MAP3K7-binding proteins 1, 2 and 3. This complex can then activate dual specificity mitogen-activated protein kinase kinase 4 (MAP2K4), which then phosphorylates mitogen-activated protein kinase 8 (MAPK8) in the cell nucleus. Alternately, the TAK1 and MAP3K7-binding complex can phosphorylate and activate mitogen-activated protein kinase 14 (MAPK14), which then phosphorylates the IKK complex.
NF-kappa-B is a transcription factor that is inhibited by NF-kappa-B inhibitor alpha, which binds to it and blocks its nuclear localization sequence, holding it in the cytoplasm rather than allowing it to enter the nucleus and transcribe the DNA. However, the IKK complex is able to phosphorylate the inhibitor, removing it and allowing nuclear factor NF-kappa-B p105 subunit and transcription factor p65 to enter the nucleus to transcribe DNA and allow the appropriate immune response for the stimulus to be activated.
Protein
PW070606
Center
PathwayVisualizationContext70882
1500
2985
#000099
PathwayVisualization70362
70482
Toll-Like Receptor Pathway 2
Toll-like receptors (TLRs) are a type of pattern recognition receptor that spans the cell membrane and recognizes conserved microbial molecules. TLRs get their name from the toll gene in Drosophila, which produces a protein that is similar in structure to TLR proteins. Each TLR is able to recognize specific unique molecules associated with pathogens, including lipoproteins, lipopolysaccharides, double stranded RNA, flagellin and others. Recognition of pathogen molecules allows the immune system to detect extracellular pathogens.
TLR2 can form heterodimers on the surface of the cell's plasma membrane with either TLR1 or TLR6. These dimers, along with another protein known as CD14 as a cofactor, can detect different microbial lipoproteins. Following binding of lipoproteins to these complexes, they activate a protein known as myeloid differentiation primary response protein (MyD88). MyD88 then joins with interleukin-1 receptor-associated kinase 1 (IRAK1) to form a complex.
TLR4 is another TLR that detects lipopolysaccharides (LPS) that make up the outer membrane of Gram-negative bacteria. It associates with two other proteins, monocyte differentiation antigen CD14, and lymphocyte antigen 96 (MD2), which allow it to better bind LPS. Once LPS has bound to the complex, it activates signalling to the toll/interleukin-1 receptor domain-containing adaptor protein (TIRAP) and Toll-interacting protein (TOLLIP), which then recruit MyD99 and IRAK1 to the TLR on the cell surface.
Other TLRs have slightly more simple pathways, including TLR9, which recognizes CpG-DNA, which is a section of DNA with a cytosine followed by a guanine and are found commonly in pathogen genomes. TLRs 3 and 8 both recognize double stranded RNA, which is found in some viruses. TLR7 recognizes single stranded RNA from internalized viral genomes, and can also be activated by the drug Imiquimod, sold as Aldara. Imiquimod is used to treat genital warts , actinic keratosis and basal cell carcinoma by activating the immune system in the area it was applied. Finally, TLR5 recognizes the bacterial flagellin proteins. When any of these substances bind their respective TLRs, the TLRs signal to the MyD88 and IRAK1 complex.
After any of these activation mechanisms occurs, the IRAK protein, which is a kinase, phosphorylates and activates TNF receptor-associated factor 6 (TRAF6). TRAF6 then interacts with the evolutionarily conserved signaling intermediate in Toll pathway (ECSIT). ECSIT then activates mitogen-activated protein kinase kinase kinase 1 (MAP3K1). This then phosphorylates the IKK complex, comprised of inhibitors of nuclear factor kappa-B kinase subunits alpha and beta (IKKA and IKKB), as well as its regulatory subunit, NF-kappa-B essential modulator (NEMO).
Another pathway starting with the activation of TRAF6 leads to this same point. First, TRAF6 activates a complex consisting of mitogen-activated protein kinase kinase kinase 7 (MAP3K7), as well as TGF-beta-activated kinase 1 (TAK1) and MAP3K7-binding proteins 1, 2 and 3. This complex can then activate dual specificity mitogen-activated protein kinase kinase 4 (MAP2K4), which then phosphorylates mitogen-activated protein kinase 8 (MAPK8) in the cell nucleus. Alternately, the TAK1 and MAP3K7-binding complex can phosphorylate and activate mitogen-activated protein kinase 14 (MAPK14), which then phosphorylates the IKK complex.
NF-kappa-B is a transcription factor that is inhibited by NF-kappa-B inhibitor alpha, which binds to it and blocks its nuclear localization sequence, holding it in the cytoplasm rather than allowing it to enter the nucleus and transcribe the DNA. However, the IKK complex is able to phosphorylate the inhibitor, removing it and allowing nuclear factor NF-kappa-B p105 subunit and transcription factor p65 to enter the nucleus to transcribe DNA and allow the appropriate immune response for the stimulus to be activated.
Protein
1
236343
25309543
Kawasaki T, Kawai T: Toll-like receptor signaling pathways. Front Immunol. 2014 Sep 25;5:461. doi: 10.3389/fimmu.2014.00461. eCollection 2014.
70482
Pathway
236344
https://www.cellsignal.com/contents/science-cst-pathways-immunology-and-inflammation/toll-like-receptors-(tlrs)-interactive-pathway/pathways-tlr
70482
Pathway
236345
https://www.genome.jp/kegg-bin/show_pathway?hsa04620
70482
Pathway
236346
https://cgap.nci.nih.gov/Pathways/BioCarta/h_tollPathway
70482
Pathway
1
Cell
CL:0000000
4
Cardiomyocyte
CL:0000746
3
Neuron
CL:0000540
7
Epithelial Cell
CL:0000066
1
Homo sapiens
9606
Eukaryote
Human
2
Bacteria
2
Prokaryote
Bacteria
12
Mus musculus
10090
Eukaryote
Mouse
3
Escherichia coli
562
Prokaryote
17
Rattus norvegicus
10116
Eukaryote
Rat
19
Schizosaccharomyces pombe
4896
Eukaryote
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
29
Saccharomyces cerevisiae (strain ATCC 204508 / S288c)
559292
Eukaryote
Baker's yeast
25
Escherichia coli (strain K12)
83333
Prokaryote
49
Bathymodiolus platifrons
220390
Eukaryote
Deep sea mussel
23
Pseudomonas aeruginosa
287
Prokaryote
60
Nitzschia sp.
0001
Eukaryote
Nitzschia4
5
Bos taurus
9913
Eukaryote
Cattle
10
Drosophila melanogaster
7227
Eukaryote
Fruit fly
5
Cytoplasm
GO:0005737
10
Cell Membrane
GO:0005886
11
Extracellular Space
GO:0005615
3
Mitochondrial Matrix
GO:0005759
4
Peroxisome
GO:0005777
13
Endoplasmic Reticulum
GO:0005783
1
Cytosol
GO:0005829
2
Mitochondrion
GO:0005739
7
Endoplasmic Reticulum Membrane
GO:0005789
19
sarcoplasmic reticulum
GO:0016529
15
Nucleus
GO:0005634
14
Mitochondrial Outer Membrane
GO:0005741
31
Periplasmic Space
GO:0005620
35
Chloroplast
GO:0009507
34
Plant-Type Vacuole
GO:0000325
12
Mitochondrial Inner Membrane
GO:0005743
32
Inner Membrane
GO:0070258
36
Membrane
GO:0016020
1
Liver
BTO:0000759
72
9
25
Intestine
BTO:0000648
8
Blood Vessel
BTO:0001102
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1
1
PW_BS000007
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PW_BS000008
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PW_BS000024
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PW_BS000015
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1
PW_BS000001
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1
PW_BS000004
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4
1
1
PW_BS000005
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13
1
1
PW_BS000018
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1
1
PW_BS000002
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1
PW_BS000003
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PW_BS000014
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1
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PW_BS000049
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1
PW_BS000010
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PW_BS000047
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PW_BS000046
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PW_BS000022
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ProteinComplex
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88888
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PW_B000095
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ProteinComplex
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ProteinComplex
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88897
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PW_B000098
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ProteinComplex
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ProteinComplex
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89141
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8388
LPS core
HMDB0013471
Lipopolysaccharides (LPS), also known as lipoglycans, are large molecules consisting of a lipid and a polysaccharide joined by a covalent bond; they are found in the outer membrane of Gram-negative bacteria, act as endotoxins and elicit strong immune responses in animals. LPS is the major component of the outer membrane of Gram-negative bacteria, contributing greatly to the structural integrity of the bacteria, and protecting the membrane from certain kinds of chemical attack. LPS also increases the negative charge of the cell membrane and helps stabilize the overall membrane structure. It is of crucial importance to gram negative bacteria, whose death results if it is mutated or removed. LPS is an endotoxin, and induces a strong response from normal animal immune systems. LPS acts as the prototypical endotoxin because it binds the CD14/TLR4/MD2 receptor complex, which promotes the secretion of pro-inflammatory cytokines in many cell types, but especially in macrophages. In Immunology, the term "LPS challenge" refers to the process of exposing a subject to an LPS which may act as a toxin. LPS is also an exogenous pyrogen (external fever-inducing substance). Being of crucial importance to gram negative bacteria, these molecules make candidate targets for new antimicrobial agents. LPS comprises three parts: 1. O antigen (or O polysaccharide). 2. Core polysaccharide. 3. Lipid A. LPS Core domain always contains an oligosaccharide component which attaches directly to lipid A and commonly contains sugars such as heptose and 3-deoxy-D-mannooctulosonic Acid (also known as KDO, keto-deoxyoctulosonate).[2] The LPS Cores of many bacteria also contain non-carbohydrate components, such as phosphate, amino acids, and ethanolamine substitutents.(from wiki). This card shows the LPS core component in E.coli.
c0338
53481794
59309
CPD0-2271
CCCCCCCCCCCCCC(=O)O[C@H](CCCCCCCCCCC)CC(=O)O[C@@H]1[C@@H](NC(=O)C[C@@H](CCCCCCCCCCC)OC(=O)CCCCCCCCCCC)[C@H](OC[C@H]2O[C@H](OP(O)(O)=O)[C@H](NC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H](OC(=O)C[C@H](O)CCCCCCCCCCC)[C@@H]2O)O[C@H](CO[C@@]2(C[C@@H](O[C@@]3(C[C@@H](O[C@@]4(C[C@@H](OP(O)(=O)OCCN)[C@H](O)[C@H](O4)[C@@H](O)CO)C(O)=O)[C@H](O)[C@H](O3)[C@@H](O)CO)C(O)=O)[C@H](OC3O[C@H]([C@@H](O)CO)[C@@H](OP(O)(=O)OP(O)(=O)OCCN)[C@H](OC4O[C@H]([C@@H](O)COC5O[C@H]([C@@H](O)CO)[C@@H](OP(O)(O)=O)[C@H](O)[C@@H]5O)[C@@H](O)[C@H](OC5O[C@H](CO[C@H]6O[C@H](CO)[C@H](O)[C@H](O)[C@H]6O)[C@@H](O)[C@H](O[C@H]6O[C@H](CO)[C@H](O)[C@H](O)[C@H]6OC6O[C@H](CO)[C@@H](O)[C@H](O)[C@H]6O[C@@H]6O[C@H](CO)[C@@H](O)[C@H](O)[C@H]6NC(C)=O)[C@H]5O)[C@@H]4O)[C@@H]3O)[C@H](O2)[C@@H](O)CO)C(O)=O)[C@H]1OP(O)(O)=O
C175H317N5O101P6
InChI=1S/C175H317N5O101P6/c1-8-14-20-26-32-38-39-45-51-57-63-69-118(202)252-98(67-61-55-49-43-36-30-24-18-12-5)77-120(204)261-152-123(180-116(200)76-97(66-60-54-48-42-35-29-23-17-11-4)251-117(201)68-62-56-50-44-37-31-25-19-13-6)160(246-91-112-130(211)151(260-119(203)75-96(192)65-59-53-47-41-34-28-22-16-10-3)122(162(257-112)280-284(236,237)238)179-115(199)74-95(191)64-58-52-46-40-33-27-21-15-9-2)259-114(150(152)277-282(230,231)232)93-248-173(170(224)225)80-107(272-174(171(226)227)78-105(128(209)144(273-174)99(193)81-181)271-175(172(228)229)79-106(276-285(239,240)249-72-70-176)129(210)145(274-175)100(194)82-182)149(148(275-173)103(197)85-185)265-167-142(223)155(159(147(264-167)102(196)84-184)279-287(243,244)281-286(241,242)250-73-71-177)268-166-141(222)154(139(220)143(262-166)104(198)90-245-164-138(219)136(217)156(278-283(233,234)235)146(263-164)101(195)83-183)266-165-140(221)153(131(212)113(258-165)92-247-163-137(218)133(214)125(206)109(87-187)254-163)267-168-158(135(216)127(208)110(88-188)255-168)270-169-157(134(215)126(207)111(89-189)256-169)269-161-121(178-94(7)190)132(213)124(205)108(86-186)253-161/h95-114,121-169,181-189,191-198,205-223H,8-93,176-177H2,1-7H3,(H,178,190)(H,179,199)(H,180,200)(H,224,225)(H,226,227)(H,228,229)(H,239,240)(H,241,242)(H,243,244)(H2,230,231,232)(H2,233,234,235)(H2,236,237,238)/t95-,96-,97-,98-,99+,100+,101+,102+,103+,104+,105-,106-,107-,108-,109-,110-,111-,112-,113-,114-,121-,122-,123-,124-,125+,126-,127+,128+,129+,130-,131-,132-,133+,134+,135+,136-,137-,138+,139-,140-,141+,142+,143-,144-,145-,146-,147-,148-,149+,150-,151-,152-,153+,154+,155-,156+,157-,158-,159-,160-,161+,162-,163+,164?,165?,166?,167?,168-,169?,173-,174-,175-/m1/s1
AAXCQFOXUJMCCW-PETQGJDISA-N
(2R,4R,5S,6R)-5-{[(3S,4R,5R,6R)-5-[({[(2-aminoethoxy)(hydroxy)phosphoryl]oxy}(hydroxy)phosphoryl)oxy]-6-[(1S)-1,2-dihydroxyethyl]-4-{[(3S,4S,5R,6R)-6-[(1S)-2-{[(3S,4R,5S,6R)-6-[(1S)-1,2-dihydroxyethyl]-3,4-dihydroxy-5-(phosphonooxy)oxan-2-yl]oxy}-1-hydroxyethyl]-4-{[(3R,4S,5R,6R)-4-{[(2R,3R,4S,5R,6R)-3-{[(3R,4S,5S,6R)-3-{[(2S,3R,4R,5S,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}-3,5-dihydroxy-6-({[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}methyl)oxan-2-yl]oxy}-3,5-dihydroxyoxan-2-yl]oxy}-3-hydroxyoxan-2-yl]oxy}-4-{[(2R,4R,5S,6R)-4-{[(2R,4R,5R,6R)-4-{[(2-aminoethoxy)(hydroxy)phosphoryl]oxy}-2-carboxy-6-[(1S)-1,2-dihydroxyethyl]-5-hydroxyoxan-2-yl]oxy}-2-carboxy-6-[(1S)-1,2-dihydroxyethyl]-5-hydroxyoxan-2-yl]oxy}-6-[(1S)-1,2-dihydroxyethyl]-2-{[(2R,3S,4R,5R,6R)-5-[(3R)-3-(dodecanoyloxy)tetradecanamido]-6-{[(2R,3S,4R,5R,6R)-3-hydroxy-5-[(3R)-3-hydroxytetradecanamido]-4-{[(3R)-3-hydroxytetradecanoyl]oxy}-6-(phosphonooxy)oxan-2-yl]methoxy}-3-(phosphonooxy)-4-{[(3R)-3-(tetradecanoyloxy)tetradecanoyl]oxy}oxan-2-yl]methoxy}oxane-2-carboxylic acid
4293.205
4290.824851063
53
(2R,4R,5S,6R)-5-{[(3S,4R,5R,6R)-5-({[2-aminoethoxy(hydroxy)phosphoryl]oxy(hydroxy)phosphoryl}oxy)-6-[(1S)-1,2-dihydroxyethyl]-4-{[(3S,4S,5R,6R)-6-[(1S)-2-{[(3S,4R,5S,6R)-6-[(1S)-1,2-dihydroxyethyl]-3,4-dihydroxy-5-(phosphonooxy)oxan-2-yl]oxy}-1-hydroxyethyl]-4-{[(3R,4S,5R,6R)-4-{[(2R,3R,4S,5R,6R)-3-{[(3R,4S,5S,6R)-3-{[(2S,3R,4R,5S,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}-3,5-dihydroxy-6-({[(2S,3R,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy}methyl)oxan-2-yl]oxy}-3,5-dihydroxyoxan-2-yl]oxy}-3-hydroxyoxan-2-yl]oxy}-4-{[(2R,4R,5S,6R)-4-{[(2R,4R,5R,6R)-4-{[2-aminoethoxy(hydroxy)phosphoryl]oxy}-2-carboxy-6-[(1S)-1,2-dihydroxyethyl]-5-hydroxyoxan-2-yl]oxy}-2-carboxy-6-[(1S)-1,2-dihydroxyethyl]-5-hydroxyoxan-2-yl]oxy}-6-[(1S)-1,2-dihydroxyethyl]-2-{[(2R,3S,4R,5R,6R)-5-[(3R)-3-(dodecanoyloxy)tetradecanamido]-6-{[(2R,3S,4R,5R,6R)-3-hydroxy-5-[(3R)-3-hydroxytetradecanamido]-4-{[(3R)-3-hydroxytetradecanoyl]oxy}-6-(phosphonooxy)oxan-2-yl]methoxy}-3-(phosphonooxy)-4-{[(3R)-3-(tetradecanoyloxy)tetradecanoyl]oxy}oxan-2-yl]methoxy}oxane-2-carboxylic acid
0
-10
Core oligosaccharide;Core oligosaccharide lipid a;Endotoxin lps core;Endotoxin lipopolysaccharide core;Lps core;Lipopolysaccharide ra component;Lipopolysaccharide core endotoxin;Ra-lps
PW_C008388
LPScore
88889
308
111663
15
9198
Imiquimod
HMDB0014862
Imiquimod is an immune response modifier that acts as a toll-like receptor 7 agonist. Imiquimod is commonly used topically to treat warts on the skin of the genital and anal areas. Imiquimod does not cure warts, and new warts may appear during treatment. Imiquimod does not fight the viruses that cause warts directly, however, it does help to relieve and control wart production. miquimod is also used to treat a skin condition of the face and scalp called actinic keratoses and certain types of skin cancer called superficial basal cell carcinoma.
99011-02-6
57469
36704
51809
DB00724
CC(C)CN1C=NC2=C1C1=CC=CC=C1N=C2N
C14H16N4
InChI=1S/C14H16N4/c1-9(2)7-18-8-16-12-13(18)10-5-3-4-6-11(10)17-14(12)15/h3-6,8-9H,7H2,1-2H3,(H2,15,17)
DOUYETYNHWVLEO-UHFFFAOYSA-N
1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine
240.3036
240.137496532
-2.99
1
imiquimod
0
0
Imiquimod acetate;1-isobutyl-1h-imidazo[4,5-c]quinolin-4-amine;4-amino-1-isobutyl-1h-imidazo(4,5-c)quinoline;R 837
PW_C009198
Imiq
88921
1
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
426
Liproproteins
ProteinComplex
ProteinComplex
PW_EC000426
Lipropr
88842
8
428
CpG-DNA
NucleicAcid
NucleicAcid
PW_EC000428
CPGDNA
88900
1
429
Double-Stranded RNA
NucleicAcid
NucleicAcid
PW_EC000429
DSR
88930
1
14661
Monocyte differentiation antigen CD14
P08571
Coreceptor for bacterial lipopolysaccharide (PubMed:1698311, PubMed:23264655). In concert with LBP, binds to monomeric lipopolysaccharide and delivers it to the LY96/TLR4 complex, thereby mediating the innate immune response to bacterial lipopolysaccharide (LPS) (PubMed:20133493, PubMed:23264655). Acts via MyD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (PubMed:8612135). Acts as a coreceptor for TLR2:TLR6 heterodimer in response to diacylated lipopeptides and for TLR2:TLR1 heterodimer in response to triacylated lipopeptides, these clusters trigger signaling from the cell surface and subsequently are targeted to the Golgi in a lipid-raft dependent pathway (PubMed:16880211). Binds electronegative LDL (LDL(-)) and mediates the cytokine release induced by LDL(-) (PubMed:23880187).
CD14
1
80816
228
81836
308
88844
8
88893
1
131696
80
14347
Toll-like receptor 2
O60603
Cooperates with LY96 to mediate the innate immune response to bacterial lipoproteins and other microbial cell wall components. Cooperates with TLR1 or TLR6 to mediate the innate immune response to bacterial lipoproteins or lipopeptides (PubMed:21078852, PubMed:17889651). Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response. May also activate immune cells and promote apoptosis in response to the lipid moiety of lipoproteins (PubMed:10426995, PubMed:10426996). Recognizes mycoplasmal macrophage-activating lipopeptide-2kD (MALP-2), soluble tuberculosis factor (STF), phenol-soluble modulin (PSM) and B.burgdorferi outer surface protein A lipoprotein (OspA-L) cooperatively with TLR6 (PubMed:11441107). Stimulation of monocytes in vitro with M.tuberculosis PstS1 induces p38 MAPK and ERK1/2 activation primarily via this receptor, but also partially via TLR4 (PubMed:16622205). MAPK activation in response to bacterial peptidoglycan also occurs via this receptor (PubMed:16622205). Acts as a receptor for M.tuberculosis lipoproteins LprA, LprG, LpqH and PstS1, some lipoproteins are dependent on other coreceptors (TLR1, CD14 and/or CD36); the lipoproteins act as agonists to modulate antigen presenting cell functions in response to the pathogen (PubMed:19362712). M.tuberculosis HSP70 (dnaK) but not HSP65 (groEL-2) acts via this protein to stimulate NF-kappa-B expression (PubMed:15809303). Recognizes M.tuberculosis major T-antigen EsxA (ESAT-6) which inhibits downstream MYD88-dependent signaling (shown in mouse) (By similarity). Forms activation clusters composed of several receptors depending on the ligand, these clusters trigger signaling from the cell surface and subsequently are targeted to the Golgi in a lipid-raft dependent pathway. Forms the cluster TLR2:TLR6:CD14:CD36 in response to diacylated lipopeptides and TLR2:TLR1:CD14 in response to triacylated lipopeptides (PubMed:16880211). Required for normal uptake of M.tuberculosis, a process that is inhibited by M.tuberculosis LppM (By similarity).
TLR2
1
80116
228
80819
8
81837
308
14351
Toll-like receptor 6
Q9Y2C9
Participates in the innate immune response to Gram-positive bacteria and fungi. Specifically recognizes diacylated and, to a lesser extent, triacylated lipopeptides (PubMed:20037584). In response to diacylated lipopeptides, forms the activation cluster TLR2:TLR6:CD14:CD36, this cluster triggers signaling from the cell surface and subsequently is targeted to the Golgi in a lipid-raft dependent pathway (PubMed:16880211). Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response. Recognizes mycoplasmal macrophage-activating lipopeptide-2kD (MALP-2), soluble tuberculosis factor (STF), phenol-soluble modulin (PSM) and B.burgdorferi outer surface protein A lipoprotein (OspA-L) cooperatively with TLR2 (PubMed:11441107). In complex with TLR4, promotes sterile inflammation in monocytes/macrophages in response to oxidized low-density lipoprotein (oxLDL) or amyloid-beta 42. In this context, the initial signal is provided by oxLDL- or amyloid-beta 42-binding to CD36. This event induces the formation of a heterodimer of TLR4 and TLR6, which is rapidly internalized and triggers inflammatory response, leading to the NF-kappa-B-dependent production of CXCL1, CXCL2 and CCL9 cytokines, via MYD88 signaling pathway, and CCL5 cytokine, via TICAM1 signaling pathway, as well as IL1B secretion (PubMed:11441107, PubMed:20037584).
TLR6
1
80119
228
80817
8
14346
Toll-like receptor 1
Q15399
Participates in the innate immune response to microbial agents. Specifically recognizes diacylated and triacylated lipopeptides. Cooperates with TLR2 to mediate the innate immune response to bacterial lipoproteins or lipopeptides (PubMed:21078852). Forms the activation cluster TLR2:TLR1:CD14 in response to triacylated lipopeptides, this cluster triggers signaling from the cell surface and subsequently is targeted to the Golgi in a lipid-raft dependent pathway (PubMed:16880211). Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response.
TLR1
1
80115
228
88863
8
14349
Myeloid differentiation primary response protein MyD88
Q99836
Adapter protein involved in the Toll-like receptor and IL-1 receptor signaling pathway in the innate immune response (PubMed:15361868, PubMed:18292575). Acts via IRAK1, IRAK2, IRF7 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (PubMed:15361868, PubMed:24316379, PubMed:19506249). Increases IL-8 transcription (PubMed:9013863). Involved in IL-18-mediated signaling pathway. Activates IRF1 resulting in its rapid migration into the nucleus to mediate an efficient induction of IFN-beta, NOS2/INOS, and IL12A genes. MyD88-mediated signaling in intestinal epithelial cells is crucial for maintenance of gut homeostasis and controls the expression of the antimicrobial lectin REG3G in the small intestine (By similarity).
MYD88
1
80118
228
80483
8
81838
308
14352
Interleukin-1 receptor-associated kinase 1
P51617
Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens. Involved in Toll-like receptor (TLR) and IL-1R signaling pathways. Is rapidly recruited by MYD88 to the receptor-signaling complex upon TLR activation. Association with MYD88 leads to IRAK1 phosphorylation by IRAK4 and subsequent autophosphorylation and kinase activation. Phosphorylates E3 ubiquitin ligases Pellino proteins (PELI1, PELI2 and PELI3) to promote pellino-mediated polyubiquitination of IRAK1. Then, the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA-IKKB complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB) leading to NF-kappa-B nuclear translocation and activation. Alternatively, phosphorylates TIRAP to promote its ubiquitination and subsequent degradation. Phosphorylates the interferon regulatory factor 7 (IRF7) to induce its activation and translocation to the nucleus, resulting in transcriptional activation of type I IFN genes, which drive the cell in an antiviral state. When sumoylated, translocates to the nucleus and phosphorylates STAT3.
IRAK1
1
2.7.11.1
80120
166
80820
228
80915
8
81839
308
14353
TNF receptor-associated factor 6
Q9Y4K3
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. Leads to the 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
1
2.3.2.27
80818
8
130893
308
134688
14
2033
Toll-like receptor 4
O00206
Cooperates with LY96 and CD14 to mediate the innate immune response to bacterial lipopolysaccharide (LPS). Acts via MYD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response
HMDBP02639
TLR4
9q33.1
AF177766
1
80480
8
80907
228
81934
308
111664
15
131697
80
136110
152
14662
Lymphocyte antigen 96
Q9Y6Y9
Binds bacterial lipopolysaccharide (LPS) (PubMed:17803912, PubMed:17569869). Cooperates with TLR4 in the innate immune response to bacterial lipopolysaccharide (LPS), and with TLR2 in the response to cell wall components from Gram-positive and Gram-negative bacteria (PubMed:11160242, PubMed:11593030). Enhances TLR4-dependent activation of NF-kappa-B (PubMed:10359581). Cells expressing both LY96 and TLR4, but not TLR4 alone, respond to LPS (PubMed:10359581).
LY96
1
80908
228
81935
308
81987
8
131698
80
14348
Toll/interleukin-1 receptor domain-containing adapter protein
P58753
Adapter involved in TLR2 and TLR4 signaling pathways in the innate immune response. Acts via IRAK2 and TRAF-6, leading to the activation of NF-kappa-B, MAPK1, MAPK3 and JNK, and resulting in cytokine secretion and the inflammatory response. Positively regulates the production of TNF-alpha and interleukin-6.
TIRAP
1
80117
228
81938
308
81990
8
14663
Toll-interacting protein
Q9H0E2
Component of the signaling pathway of IL-1 and Toll-like receptors. Inhibits cell activation by microbial products. Recruits IRAK1 to the IL-1 receptor complex. Inhibits IRAK1 phosphorylation and kinase activity (PubMed:11751856). Connects the ubiquitin pathway to autophagy by functioning as a ubiquitin-ATG8 family adapter and thus mediating autophagic clearance of ubiquitin conjugates. The TOLLIP-dependent selective autophagy pathway plays an important role in clearance of cytotoxic polyQ proteins aggregates (PubMed:25042851).
TOLLIP
1
80909
228
81936
308
81988
8
2085
Toll-like receptor 9
Q9NR96
Key component of innate and adaptive immunity. TLRs (Toll-like receptors) control host immune response against pathogens through recognition of molecular patterns specific of microorganisms. TLR9 is a nucleotide-sensing TLR which is activated by unmethylated cytidine-phosphate-guanosine (CpG) dinucleotides. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response
HMDBP02761
TLR9
3p21.3
EU170542
1
82554
8
88904
1
14692
Toll-like receptor 7
Q9NYK1
Key component of innate and adaptive immunity. TLRs (Toll-like receptors) control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. TLR7 is a nucleotide-sensing TLR which is activated by single-stranded RNA. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (By similarity).
TLR7
1
82569
8
88922
1
14691
Toll-like receptor 3
O15455
Key component of innate and adaptive immunity. TLRs (Toll-like receptors) control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. TLR3 is a nucleotide-sensing TLR which is activated by double-stranded RNA, a sign of viral infection. Acts via the adapter TRIF/TICAM1, leading to NF-kappa-B activation, IRF3 nuclear translocation, cytokine secretion and the inflammatory response.
TLR3
1
82557
8
14713
Flagellin
P04949
Flagellin is the subunit protein which polymerizes to form the filaments of bacterial flagella.
fliC
25
88944
1
14714
Toll-like receptor 5
O60602
Participates in the innate immune response to microbial agents. Mediates detection of bacterial flagellins. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response.
TLR5
1
88945
1
14715
Toll-like receptor 8
Q9NR97
Key component of innate and adaptive immunity. TLRs (Toll-like receptors) control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response.
TLR8
1
88950
1
14354
Evolutionarily conserved signaling intermediate in Toll pathway, mitochondrial
Q9BQ95
Adapter protein of the Toll-like and IL-1 receptor signaling pathway that is involved in the activation of NF-kappa-B via MAP3K1. Promotes proteolytic activation of MAP3K1. Involved in the BMP signaling pathway. Required for normal embryonic development (By similarity).
ECSIT
1
80821
8
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
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
8561
Transcription factor p65
Q04206
NF-kappa-B is a pleiotropic transcription factor present in almost all cell types and is the endpoint of a series of signal transduction events that are initiated by a vast array of stimuli related to many biological processes 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 p65-c-Rel complexes are transcriptional activators. The NF-kappa-B p65-p65 complex appears to be involved in invasin-mediated activation of IL-8 expression. The inhibitory effect of I-kappa-B upon NF-kappa-B the cytoplasm is exerted primarily through the interaction with p65. p65 shows a weak DNA-binding site which could contribute directly to DNA binding in the NF-kappa-B complex. Associates with chromatin at the NF-kappa-B promoter region via association with DDX1. Essential for cytokine gene expression in T-cells (PubMed:15790681).
RELA
1
80143
8
81923
23
5773
NF-kappa-B inhibitor alpha
P25963
NFKBIA
1
4135
2
4172
23
80142
8
14355
Mitogen-activated protein kinase kinase kinase 7
O43318
Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Plays an important role in the cascades of cellular responses evoked by changes in the environment. Mediates signal transduction of TRAF6, various cytokines including interleukin-1 (IL-1), transforming growth factor-beta (TGFB), TGFB-related factors like BMP2 and BMP4, toll-like receptors (TLR), tumor necrosis factor receptor CD40 and B-cell receptor (BCR). Ceramides are also able to activate MAP3K7/TAK1. Once activated, acts as an upstream activator of the MKK/JNK signal transduction cascade and the p38 MAPK signal transduction cascade through the phosphorylation and activation of several MAP kinase kinases like MAP2K1/MEK1, MAP2K3/MKK3, MAP2K6/MKK6 and MAP2K7/MKK7. These MAP2Ks in turn activate p38 MAPKs, c-jun N-terminal kinases (JNKs) and I-kappa-B kinase complex (IKK). Both p38 MAPK and JNK pathways control the transcription factors activator protein-1 (AP-1), while nuclear factor-kappa B is activated by IKK. MAP3K7 activates also IKBKB and MAPK8/JNK1 in response to TRAF6 signaling and mediates BMP2-induced apoptosis. In osmotic stress signaling, plays a major role in the activation of MAPK8/JNK1, but not that of NF-kappa-B. Promotes TRIM5 capsid-specific restriction activity.
MAP3K7
1
2.7.11.25
80501
8
8630
TGF-beta-activated kinase 1 and MAP3K7-binding protein 2
Q9NYJ8
Adapter linking MAP3K7/TAK1 and TRAF6. Promotes MAP3K7 activation in the IL1 signaling pathway. The binding of 'Lys-63'-linked polyubiquitin chains to TAB2 promotes autophosphorylation of MAP3K7 at 'Thr-187'. Involved in heart development.
TAB2
1
80822
8
8629
TGF-beta-activated kinase 1 and MAP3K7-binding protein 1
Q15750
May be an important signaling intermediate between TGFB receptors and MAP3K7/TAK1. May play an important role in mammalian embryogenesis.
TAB1
1
80502
8
9582
TGF-beta-activated kinase 1 and MAP3K7-binding protein 3
Q8N5C8
Adapter linking MAP3K7/TAK1 and TRAF6 or TRAF2. Mediator of MAP3K7 activation, respectively in the IL1 and TNF signaling pathways. Plays a role in activation of NF-kappa-B and AP1 transcription factor. Isoform 2 may be an oncogenic factor.
TAB3
1
89145
8
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
14690
Dual specificity mitogen-activated protein kinase kinase 4
P45985
Dual specificity protein kinase which acts as an essential component of the MAP kinase signal transduction pathway. Essential component of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway. With MAP2K7/MKK7, is the one of the only known kinase to directly activate the stress-activated protein kinase/c-Jun N-terminal kinases MAPK8/JNK1, MAPK9/JNK2 and MAPK10/JNK3. MAP2K4/MKK4 and MAP2K7/MKK7 both activate the JNKs by phosphorylation, but they differ in their preference for the phosphorylation site in the Thr-Pro-Tyr motif. MAP2K4 shows preference for phosphorylation of the Tyr residue and MAP2K7/MKK7 for the Thr residue. The phosphorylation of the Thr residue by MAP2K7/MKK7 seems to be the prerequisite for JNK activation at least in response to proinflammatory cytokines, while other stimuli activate both MAP2K4/MKK4 and MAP2K7/MKK7 which synergistically phosphorylate JNKs. MAP2K4 is required for maintaining peripheral lymphoid homeostasis. The MKK/JNK signaling pathway is also involved in mitochondrial death signaling pathway, including the release cytochrome c, leading to apoptosis. Whereas MAP2K7/MKK7 exclusively activates JNKs, MAP2K4/MKK4 additionally activates the p38 MAPKs MAPK11, MAPK12, MAPK13 and MAPK14.
MAP2K4
1
2.7.12.2
82101
8
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
7945
Toll-like receptor 4
1
PW_P007945
16081
2033
88884
8
7946
Lymphocyte antigen 96
1
PW_P007946
16082
14662
88887
7
7543
Toll/interleukin-1 receptor domain-containing adapter protein
1
PW_P007543
15419
14348
1
7947
Toll-interacting protein
1
PW_P007947
16083
14663
88896
8
7550
Mitogen-activated protein kinase kinase kinase 7
1
PW_P007550
15426
14355
1
7974
TAB Complex
1
PW_P007974
16127
8630
16128
8629
16129
9582
89140
8
7810
Monocyte differentiation antigen CD14
1
PW_P007810
15845
14661
7940
TLR2,6
1
PW_P007940
16072
14347
16073
14351
88853
8
7941
TLR1,2
1
PW_P007941
16074
14347
16075
14346
88862
8
7944
MYD88,IRAK (myddosome)
1
PW_P007944
16079
14349
16080
14352
88872
8
7548
TNF receptor-associated factor 6
1
PW_P007548
15424
14353
1
7948
Toll-like receptor 9
1
PW_P007948
16084
2085
88903
308
7949
Toll-like receptor 7
1
PW_P007949
16085
14692
88920
308
7950
Toll-like receptor 3
1
PW_P007950
16086
14691
88931
8
7951
Flagellin
25
PW_P007951
16087
14713
88940
1
7952
Toll-like receptor 5
1
PW_P007952
16088
14714
88943
308
7953
Toll-like receptor 8
1
PW_P007953
16089
14715
88949
308
7954
Evolutionarily conserved signaling intermediate in Toll pathway, mitochondrial
1
PW_P007954
16090
14354
88969
8
7833
Mitogen-activated protein kinase kinase kinase 1 without Magnesium
1
PW_P007833
15876
1067
80887
8
7955
Inhibitor of nuclear factor kappa-B kinase
1
PW_P007955
16091
1749
16092
1222
16093
8558
88976
8
7715
NFKBIA, NFKB1, RELA complex
1
PW_P007715
15671
1808
15672
8561
15673
5773
80531
8
7716
NFKB1,RELA complex
1
PW_P007716
15674
1808
15675
8561
80532
8
7780
NFKBIA with phosphate
1
PW_P007780
15798
5773
799
1104
80733
8
7890
Mitogen-activated protein kinase kinase kinase 14
1
PW_P007890
15979
1405
811
1104
7896
Dual specificity mitogen-activated protein kinase kinase 4 and Phosphate
1
PW_P007896
15988
14690
813
1104
7834
Mitogen-activated protein kinase 8 without Magnesium
1
PW_P007834
15877
1424
80888
8
118800
PW_R118800
Right
435179
7715
1
ProteinComplex
false
435180
7716
1
ProteinComplex
false
435181
7780
1
ProteinComplex
false
848
Activation
PW_I000848
1695
426
ElementCollection
1
1696
7810
ProteinComplex
1
849
Activation
PW_I000849
1697
426
ElementCollection
1
1698
7940
ProteinComplex
1
850
Activation
PW_I000850
1699
7810
ProteinComplex
1
1700
7940
ProteinComplex
1
851
Activation
PW_I000851
1701
426
ElementCollection
1
1702
7941
ProteinComplex
1
852
Activation
PW_I000852
1703
7810
ProteinComplex
1
1704
7941
ProteinComplex
1
853
Activation
PW_I000853
1705
7941
ProteinComplex
1
1706
7944
ProteinComplex
1
854
Activation
PW_I000854
1707
7940
ProteinComplex
1
1708
7944
ProteinComplex
1
855
Activation
PW_I000855
1709
7944
ProteinComplex
1
1710
7548
ProteinComplex
1
856
Activation
PW_I000856
1711
8388
Compound
1
1712
94
Bound
1
857
Activation
PW_I000857
1713
8388
Compound
1
1714
7810
ProteinComplex
1
858
Activation
PW_I000858
1715
7810
ProteinComplex
1
1716
94
Bound
1
859
Activation
PW_I000859
1717
94
Bound
1
1718
95
Bound
1
860
Activation
PW_I000860
1719
95
Bound
1
1720
7944
ProteinComplex
1
861
Activation
PW_I000861
1721
428
ElementCollection
1
1722
7948
ProteinComplex
1
862
Activation
PW_I000862
1723
9198
Compound
1
1724
7949
ProteinComplex
1
863
Activation
PW_I000863
1725
429
ElementCollection
1
1726
7950
ProteinComplex
1
864
Activation
PW_I000864
1727
7951
ProteinComplex
1
1728
7952
ProteinComplex
1
865
Activation
PW_I000865
1729
429
ElementCollection
1
1730
7953
ProteinComplex
1
866
Activation
PW_I000866
1731
7948
ProteinComplex
1
1732
7944
ProteinComplex
1
867
Activation
PW_I000867
1733
7950
ProteinComplex
1
1734
7944
ProteinComplex
1
868
Activation
PW_I000868
1735
7953
ProteinComplex
1
1736
7944
ProteinComplex
1
869
Activation
PW_I000869
1737
7949
ProteinComplex
1
1738
7944
ProteinComplex
1
870
Activation
PW_I000870
1739
7952
ProteinComplex
1
1740
7944
ProteinComplex
1
871
Activation
PW_I000871
1741
7548
ProteinComplex
1
1742
7954
ProteinComplex
1
872
Activation
PW_I000872
1743
7954
ProteinComplex
1
1744
7833
ProteinComplex
1
873
Activation
PW_I000873
1745
7833
ProteinComplex
1
1746
7955
ProteinComplex
1
874
Activation
PW_I000874
1747
7955
ProteinComplex
1
1748
7715
ProteinComplex
1
892
Activation
PW_I000892
1783
7548
ProteinComplex
1
1784
98
Bound
1
893
Activation
PW_I000893
1785
98
Bound
1
1786
7890
ProteinComplex
1
894
Activation
PW_I000894
1787
7890
ProteinComplex
1
1788
7955
ProteinComplex
1
896
Activation
PW_I000896
1791
98
Bound
1
1792
7896
ProteinComplex
1
898
Activation
PW_I000898
1795
7896
ProteinComplex
1
1796
7834
ProteinComplex
1
501
94
308
70362
803
517513
2327582
804
517514
2327583
502
95
8
70362
805
517540
2327702
806
517541
2327703
505
98
8
70362
815
518879
2333712
816
518880
2333713
1707649
8388
308
3
false
1473
52
10
regular
100
100
1708135
9198
1
156
false
2436
47
10
regular
100
100
1711630
1104
8
9
false
1347
1200
10
regular
100
25
1712196
1104
8
9
false
1352
929
19
regular
100
25
1712316
1104
8
9
false
2372
929
20
regular
100
25
9897
426
37
8
false
647
47
12
regular
100
90
9899
428
37
1
false
1836
50
12
regular
100
90
9900
429
37
8
false
2138
47
12
regular
100
90
630349
2033
308
80
false
1283
232
8
subunit
regular
200
130
630350
14662
308
2
false
1323
347
8
subunit
regular
150
70
630376
14348
8
2
false
1588
372
8
subunit
regular
150
70
630377
14663
8
2
false
1588
432
8
subunit
regular
150
70
631745
14355
8
2
false
2462
682
8
subunit
regular
150
70
631746
8630
8
2
false
2462
742
8
subunit
regular
150
70
631747
8629
8
2
false
2347
707
8
subunit
regular
150
70
631748
9582
8
2
false
2347
767
8
subunit
regular
150
70
630056
14661
8
2
false
622
282
8
subunit
regular
150
70
630129
14347
8
80
false
832
232
8
subunit
regular
200
130
630130
14351
8
80
false
992
232
8
subunit
regular
200
130
630180
14347
8
80
false
332
227
8
subunit
regular
200
130
630181
14346
8
80
false
172
227
8
subunit
regular
200
130
630253
14349
8
2
false
622
497
8
subunit
regular
150
70
630254
14352
8
2
false
622
557
8
subunit
regular
150
70
630286
14353
8
2
false
1322
767
8
subunit
regular
150
70
630368
14661
1
2
false
1588
282
8
subunit
regular
150
70
630378
14349
8
2
false
1323
497
8
subunit
regular
150
70
630379
14352
8
2
false
1323
557
8
subunit
regular
150
70
630416
2085
1
80
false
1781
230
8
subunit
regular
200
130
630499
14692
1
80
false
2381
227
8
subunit
regular
200
130
630551
14691
8
80
false
1983
227
8
subunit
regular
200
130
630621
14713
1
2
false
2605
64
8
subunit
regular
150
70
630622
14714
1
80
false
2575
224
8
subunit
regular
200
130
630645
14715
1
80
false
2183
227
8
subunit
regular
200
130
630667
14349
8
2
false
2231
500
8
subunit
regular
150
70
630668
14352
8
2
false
2236
560
8
subunit
regular
150
70
630746
14354
8
2
false
977
767
8
subunit
regular
150
70
630763
1067
8
2
false
622
767
8
subunit
regular
150
70
630808
1749
8
2
false
622
912
8
subunit
regular
150
70
630809
1222
8
2
false
622
972
8
subunit
regular
150
70
630810
8558
8
2
false
727
942
8
subunit
regular
150
70
630868
1808
8
2
false
622
1112
8
subunit
regular
150
70
630869
8561
8
2
false
622
1172
8
subunit
regular
150
70
630870
5773
8
2
false
722
1142
8
subunit
regular
150
70
631586
1808
8
2
false
1982
1085
8
subunit
regular
150
70
631587
8561
8
2
false
1982
1140
8
subunit
regular
150
70
631588
5773
8
2
false
1322
1215
8
subunit
regular
150
70
631768
1405
8
2
false
1327
944
8
subunit
regular
150
70
631807
14690
8
2
false
2347
949
8
subunit
regular
150
70
631827
1424
8
2
false
2047
946
8
subunit
regular
150
70
517513
7945
70362
308
628843
630349
517514
7946
70362
308
628844
630350
517540
7543
70362
8
628870
630376
517541
7947
70362
8
628871
630377
518879
7550
70362
8
630237
631745
518880
7974
70362
8
630238
631746
630239
631747
630240
631748
517244
7810
70362
8
628550
630056
517305
7940
70362
8
628623
630129
628624
630130
517355
7941
70362
8
628674
630180
628675
630181
517420
7944
70362
8
628747
630253
628748
630254
517450
7548
70362
8
628780
630286
517532
7810
70362
1
628862
630368
517542
7944
70362
8
628872
630378
628873
630379
517579
7948
70362
1
628910
630416
517662
7949
70362
1
628993
630499
517714
7950
70362
8
629045
630551
517784
7951
70362
1
629115
630621
517785
7952
70362
1
629116
630622
517808
7953
70362
1
629139
630645
517830
7944
70362
8
629161
630667
629162
630668
517908
7954
70362
8
629240
630746
517925
7833
70362
8
629257
630763
517969
7955
70362
8
629302
630808
629303
630809
629304
630810
518027
7715
70362
8
629362
630868
629363
630869
629364
630870
518723
7716
70362
8
630078
631586
630079
631587
518724
7780
70362
8
630080
631588
8469
1711630
2333017
Cofactor
518900
7890
70362
8
630260
631768
8474
1712196
2333797
Cofactor
518939
7896
70362
8
630299
631807
8475
1712316
2333965
Cofactor
518958
7834
70362
8
630319
631827
2326377
M697 282 C697 245 698 202 697 147
149
false
18
true
M 570.9468550441649 843.261556296296 L 556 842 L 562.3808877211858 855.5751343230784
false
2326378
M737 42 C767 42 197 -13 227 -13
149
true
18
2326647
M1032 302 C1033 266 1031 237 1031 198 C1006 199 725 202 697 201 C697 175 697 164 697 147
149
false
18
true
M 570.9468550441649 852.261556296296 L 556 851 L 562.3808877211858 864.5751343230784
false
false
false
2326648
M747 97 C777 97 789.5 37 819.5 37
149
true
18
2326727
M772 317 C802 317 809.5 267 839.5 267
149
true
18
2326728
M1032 302 C1032 325 1034 299 1034 321 C1011 321 794 317 772 317
149
false
18
true
M 570.9468550441649 852.261556296296 L 556 851 L 562.3808877211858 864.5751343230784
false
2326875
M372 297 C371 258 370 227 370 200 C408 200 665 202 696 202 C696 164 697 186 697 147
149
false
18
true
M 509.94685504416486 852.261556296296 L 495 851 L 501.38088772118584 864.5751343230784
false
2326876
M747 97 C777 97 789.5 37 819.5 37
149
true
18
2326954
M772 317 C802 317 414.5 267 444.5 267
149
true
18
2326955
M372 297 C371 308 371 296 371 316 C401 317 589 316 622 317
149
false
18
true
M 509.94685504416486 852.261556296296 L 495 851 L 501.38088772118584 864.5751343230784
false
2327162
M372 297 C402 297 254.5 347 284.5 347
149
true
18
2327163
M622 592 C592 592 412 591 370 591 C370 564 372 397 372 297
149
false
18
true
M 557.9468550441649 852.261556296296 L 543 851 L 549.3808877211858 864.5751343230784
false
2327206
M1192 302 C1222 302 887 322 917 322
149
true
18
2327207
M772 592 C822 592 999 592 1034 591 C1034 562 1032 402 1032 302
149
false
18
true
M 557.9468550441649 1020.261556296296 L 543 1019 L 549.3808877211858 1032.5751343230784
false
2327294
M772 592 C802 592 792 457 822 457
149
true
18
2327295
M1397 767 C1396 729 1397 734 1397 699 C1365 699 726 700 696 699 C696 668 696 659 697 627
149
false
18
true
M 557.9468550441649 1051.261556296296 L 543 1050 L 549.3808877211858 1063.5751343230784
false
2327581
M1573 102 C1603 102 1538 182 1568 182
149
true
18
2327582
M1493 207 L1493 257 L1543 207 z
10
true
18
2327583
M1518 327 L1518 377 L1568 327 z
10
true
18
2327584
M1388 257 C1388 227 1387 225 1387 199 C1414 199 1496 201 1523 200 C1523 176 1522 176 1523 152
149
false
18
true
M 1036.9468550441647 973.261556296296 L 1022 972 L 1028.380887721186 985.5751343230784
false
2327665
M1573 102 C1603 102 1645.5 32 1675.5 32
149
true
18
2327666
M1663 282 C1662 245 1663 232 1663 200 C1637 199 1551 202 1522 201 C1522 177 1522 199 1523 152
149
false
18
true
M 1036.9468550441647 638.261556296296 L 1022 637 L 1028.380887721186 650.5751343230784
false
2327695
M1738 317 C1768 317 1715.5 287 1745.5 287
149
true
18
2327696
M1473 382 C1473 352 1473 338 1472 316 C1493 316 1566 317 1588 317
149
false
18
true
M 1521.9468550441647 638.261556296296 L 1507 637 L 1513.380887721186 650.5751343230784
false
2327701
M1473 382 C1503 382 1730.5 307 1760.5 307
149
true
18
2327702
M1738 452 L1738 502 L1788 452 z
10
true
18
2327703
M1738 512 L1738 562 L1788 512 z
10
true
18
2327704
M1588 467 C1558 467 1429 469 1399 469 C1399 441 1399 437 1398 417
149
false
18
true
M 1521.9468550441647 1033.261556296296 L 1507 1032 L 1513.380887721186 1045.5751343230784
false
2327707
M1323 592 C1293 592 1998 522 1968 522
149
true
18
true
M 1521.9468550441647 1033.261556296296 L 1507 1032 L 1513.380887721186 1045.5751343230784
false
2327708
M1663 502 C1663 521 1663 506 1663 530 C1638 531 1508 531 1473 532
149
false
18
true
M 2473.0096189432334 1422.5 L 2486 1415 L 2473.0096189432334 1407.5
false
2327711
M1473 592 C1503 592 1450 692 1480 692
149
true
18
2327712
M1397 767 C1397 742 1397 655 1398 627
149
false
18
true
M 1521.9468550441647 1209.261556296296 L 1507 1208 L 1513.380887721186 1221.5751343230784
false
2327879
M1886 255 C1886 218 1887 185 1886 150
149
false
18
true
M 1714.9468550441647 851.261556296296 L 1700 850 L 1706.380887721186 863.5751343230784
false
2327880
M1936 100 C1966 100 1341 -5 1371 -5
149
true
18
2328253
M2536 97 C2566 97 2456 67 2486 67
149
true
18
2328254
M2486 252 C2485 215 2487 206 2486 147
149
false
18
true
M 1714.9468550441647 718.261556296296 L 1700 717 L 1706.380887721186 730.5751343230784
false
2328489
M2088 252 C2088 224 2088 228 2088 198 C2114 198 2158 199 2188 199 C2187 172 2188 177 2188 157
149
false
18
true
M 1821.9468550441647 923.261556296296 L 1807 922 L 1813.380887721186 935.5751343230784
false
2328490
M2238 102 C2268 102 2358 117 2388 117
149
true
18
2328808
M2765 -36 C2795 -36 1735 -101 1765 -101
149
true
18
2328809
M2680 249 C2680 210 2681 172 2680 134
149
false
18
true
M 2083.9468550441647 770.261556296296 L 2069 769 L 2075.380887721186 782.5751343230784
false
2328907
M2288 252 C2287 224 2289 226 2288 198 C2262 198 2212 199 2187 199 C2187 174 2187 186 2188 157
149
false
18
true
M 2083.9468550441647 693.261556296296 L 2069 692 L 2075.380887721186 705.5751343230784
false
2328908
M2238 102 C2268 102 2390.5 -8 2420.5 -8
149
true
18
2329007
M2156 265 C2186 265 2201 265 2231 265
149
true
18
2329009
M2306 500 C2305 466 2308 444 2307 421 C2275 421 1936 422 1906 422 C1906 392 1906 391 1906 345
149
false
18
true
M 2083.9468550441647 945.261556296296 L 2069 944 L 2075.380887721186 957.5751343230784
false
2329038
M2333 267 C2363 267 2287 267 2317 267
149
true
18
2329039
M2306 500 C2307 468 2307 452 2307 421 C2275 422 2136 421 2109 421 C2108 392 2108 367 2108 342
149
false
18
true
M 2083.9468550441647 945.261556296296 L 2069 944 L 2075.380887721186 957.5751343230784
false
2329074
M2528 257 C2558 257 2384.5 257 2414.5 257
149
true
18
2329075
M2306 500 C2306 457 2308 407 2308 342
149
false
18
true
M 2083.9468550441647 945.261556296296 L 2069 944 L 2075.380887721186 957.5751343230784
false
2329108
M2696 237 C2726 237 2468.5 237 2498.5 237
149
true
18
2329109
M2306 500 C2306 470 2308 451 2307 420 C2335 421 2478 422 2506 421 C2507 396 2506 369 2506 342
149
false
18
true
M 2083.9468550441647 945.261556296296 L 2069 944 L 2075.380887721186 957.5751343230784
false
2329148
M2855 249 C2885 249 2548 249 2578 249
149
true
18
2329149
M2306 500 C2306 471 2306 463 2307 421 C2342 421 2670 424 2699 423 C2699 397 2699 361 2700 339
149
false
18
true
M 2083.9468550441647 945.261556296296 L 2069 944 L 2075.380887721186 957.5751343230784
false
2329210
M2386 595 C2416 595 1609 630 1639 630
149
true
18
2329211
M1397 767 C1397 732 1397 728 1397 699 C1429 698 2279 696 2312 697 C2311 666 2311 654 2311 630
149
false
18
true
M 1581.9468550441647 1199.261556296296 L 1567 1198 L 1573.380887721186 1211.5751343230784
false
2329372
M1472 802 C1502 802 1422 812 1452 812
149
true
18
2329373
M1127 802 C1187 801 1257 802 1322 802
149
false
18
true
M 1090.9468550441647 1547.261556296296 L 1076 1546 L 1082.380887721186 1559.5751343230784
false
2329444
M1127 802 C1157 802 1027 812 1057 812
149
true
18
2329445
M772 802 C854 800 914 801 977 802
149
false
18
true
M 852.9468550441649 1435.261556296296 L 838 1434 L 844.3808877211858 1447.5751343230784
false
2329644
M772 802 C802 802 747 822 777 822
149
true
18
2329645
M697 912 C696 868 697 889 697 837
149
false
18
true
M 852.9468550441649 1435.261556296296 L 838 1434 L 844.3808877211858 1447.5751343230784
false
2329906
M877 977 C907 977 762 1112 792 1112
149
true
18
2329908
M697 1112 C697 1052 697 1128 697 1042
149
false
18
true
M 852.9468550441649 1573.261556296296 L 838 1572 L 844.3808877211858 1585.5751343230784
false
2333015
M872 1177 C902 1177 747 1392 777 1392
5
true
18
2333016
M1982 1175 C1776 1175 990 1178 872 1177
5
false
18
true
M 852.9468550441649 1745.261556296296 L 838 1744 L 844.3808877211858 1757.5751343230784
false
2333017
M872 1280.75 L872 1330.75 L922 1280.75 z
10
true
18
2333019
M1322 1250 C1292 1250 827 1246 797 1246 C797 1222 797 1234 797 1212
5
false
18
true
M 852.9468550441649 1745.261556296296 L 838 1744 L 844.3808877211858 1757.5751343230784
false
2333711
M1472 802 C1502 802 1422 812 1452 812
149
true
18
2333712
M1772 757 L1772 807 L1822 757 z
10
true
18
2333713
M1772 817 L1772 867 L1822 817 z
10
true
18
2333714
M2347 802 C2317 802 1502 802 1472 802
149
false
18
true
M 852.9468550441649 1344.261556296296 L 838 1343 L 844.3808877211858 1356.5751343230784
false
2333797
M1367 954 L1367 1004 L1417 954 z
10
true
18
2333798
M1352 1014 C1322 1014 2032 887 2002 887
149
true
18
true
M 1272.9468550441647 1464.261556296296 L 1258 1463 L 1264.380887721186 1476.5751343230784
false
2333799
M2422 837 C2422 872 2422 848 2422 888 C2376 888 1449 887 1401 887 C1401 909 1401 917 1402 944
149
false
18
true
M 2507.0096189432334 1787.5 L 2520 1780 L 2507.0096189432334 1772.5
false
2333872
M1477 979 C1507 979 1002 1001.5 1032 1001.5
149
true
18
2333873
M877 977 C965 979 1270 977 1327 979
149
false
18
true
M 916.9468550441649 1464.261556296296 L 902 1463 L 908.3808877211858 1476.5751343230784
false
2333965
M1567 1169 L1567 1219 L1617 1169 z
10
true
18
2333966
M2347 984 C2317 984 2032 887 2002 887
149
true
18
true
M 1343.9468550441647 1622.261556296296 L 1329 1621 L 1335.380887721186 1634.5751343230784
false
2333967
M2422 837 C2423 884 2423 912 2422 949
149
false
18
true
M 2507.0096189432334 1787.5 L 2520 1780 L 2507.0096189432334 1772.5
false
2334051
M2497 984 C2527 984 1742 1216.5 1772 1216.5
149
true
18
2334052
M2197 981 C2229 981 2289 983 2347 984
149
false
18
true
M 1343.9468550441647 1710.261556296296 L 1329 1709 L 1335.380887721186 1722.5751343230784
false
523770
70362
118800
8
11027
518027
2333015
Left
11028
518723
2333016
Right
11029
518724
2333019
Right
2306
848
70362
8
459
9897
2326378
Left
2807
517244
2326377
Right
2307
849
70362
8
460
9897
2326648
Left
2808
517305
2326647
Right
2308
850
70362
8
2809
517244
2326727
Left
2810
517305
2326728
Right
2309
851
70362
8
461
9897
2326876
Left
2811
517355
2326875
Right
2310
852
70362
8
2812
517244
2326954
Left
2813
517355
2326955
Right
2311
853
70362
8
2814
517355
2327162
Left
2815
517420
2327163
Right
2312
854
70362
8
2816
517305
2327206
Left
2817
517420
2327207
Right
2313
855
70362
8
2818
517420
2327294
Left
2819
517450
2327295
Right
2314
856
70362
308
622
501
2327584
Right
719
1707649
2327581
Left
2315
857
70362
1
720
1707649
2327665
Left
2820
517532
2327666
Right
2316
858
70362
308
623
501
2327696
Right
2821
517532
2327695
Left
2317
859
70362
8
624
501
2327701
Left
625
502
2327704
Right
2318
860
70362
8
626
502
2327708
Left
2822
517542
2327707
Right
2319
855
70362
8
2823
517542
2327711
Left
2824
517450
2327712
Right
2320
861
70362
1
462
9899
2327880
Left
2825
517579
2327879
Right
2321
862
70362
1
721
1708135
2328253
Left
2826
517662
2328254
Right
2322
863
70362
8
463
9900
2328490
Left
2827
517714
2328489
Right
2323
864
70362
1
2828
517784
2328808
Left
2829
517785
2328809
Right
2324
865
70362
1
464
9900
2328908
Left
2830
517808
2328907
Right
2325
866
70362
8
2831
517579
2329007
Left
2832
517830
2329009
Right
2326
867
70362
8
2833
517714
2329038
Left
2834
517830
2329039
Right
2327
868
70362
8
2835
517808
2329074
Left
2836
517830
2329075
Right
2328
869
70362
8
2837
517662
2329108
Left
2838
517830
2329109
Right
2329
870
70362
8
2839
517785
2329148
Left
2840
517830
2329149
Right
2330
855
70362
8
2841
517830
2329210
Left
2842
517450
2329211
Right
2331
871
70362
8
2843
517450
2329372
Left
2844
517908
2329373
Right
2332
872
70362
8
2845
517908
2329444
Left
2846
517925
2329445
Right
2334
873
70362
8
2849
517925
2329644
Left
2850
517969
2329645
Right
2335
874
70362
8
2851
517969
2329906
Left
2852
518027
2329908
Right
2357
892
70362
8
634
505
2333714
Right
2885
517450
2333711
Left
2358
893
70362
8
635
505
2333799
Left
2886
518900
2333798
Right
2359
894
70362
8
2887
518900
2333872
Left
2888
517969
2333873
Right
2361
896
70362
8
636
505
2333967
Left
2891
518939
2333966
Right
2363
898
70362
8
2894
518939
2334051
Left
2895
518958
2334052
Right
114614
1869
916
1.4
1.4
0
2
14
327
267
334104
M125 403 C125 353 175 303 225 303 C990 303 1983 303 2748 303 C2798 303 2848 353 2848 403 C2848 661 2848 998 2848 1256 C2848 1306 2798 1356 2748 1356 C1983 1356 990 1356 225 1356 C175 1356 125 1306 125 1256 C125 998 125 661 125 403
1
true
6
2723.0
1053.0
408636
15
Nucleus
2169
1047
20
1.6
1.6
160
15
408637
15
Cytoplasm
185
1210
20
1.6
1.6
160
15