64625PathwayAhr Signal Transduction PathwayThe aryl hydrocarbon receptor, known as AHR, is a normally cytosolic transcription factor that can bind to foreign compounds such as flavonoids and indoles from foods, as well as synthetic ligands including polychlorobiphenyls (PCBs) and polychlorinated dibenzo-p-dioxins (PCDD). This includes 2,3,7,8-tetrachlorodibenzodioxin (TCDD), which is the ligand shown in this pathway.
AHR interacts with heat shock protein 90 (HSP90AA1), which acts as a chaperone for it. After this association, the ligand, in this case TCDD, can form a covalent bond with the complex in the cell's cytoplasm. This binding causes AHR and the rest of the complex to translocate into the nucleus of the cell. Once in the nucleus, the heat shock protein dissociates, leaving binding sites which the AHR nuclear translocator (ARNT) then binds to. Finally, the AHR/ARNT complex can interact, either directly or indirectly, with the DNA, in this case specifically a dioxin response element. With other ligands, the complex will bind to the equivalent DNA that corresponds to the genes that allow metabolism of the ligand.ProteinPW064763CenterPathwayVisualizationContext6503911391528#000099PathwayVisualization6450964625Ahr Signal Transduction PathwayThe aryl hydrocarbon receptor, known as AHR, is a normally cytosolic transcription factor that can bind to foreign compounds such as flavonoids and indoles from foods, as well as synthetic ligands including polychlorobiphenyls (PCBs) and polychlorinated dibenzo-p-dioxins (PCDD). This includes 2,3,7,8-tetrachlorodibenzodioxin (TCDD), which is the ligand shown in this pathway.
AHR interacts with heat shock protein 90 (HSP90AA1), which acts as a chaperone for it. After this association, the ligand, in this case TCDD, can form a covalent bond with the complex in the cell's cytoplasm. This binding causes AHR and the rest of the complex to translocate into the nucleus of the cell. Once in the nucleus, the heat shock protein dissociates, leaving binding sites which the AHR nuclear translocator (ARNT) then binds to. Finally, the AHR/ARNT complex can interact, either directly or indirectly, with the DNA, in this case specifically a dioxin response element. With other ligands, the complex will bind to the equivalent DNA that corresponds to the genes that allow metabolism of the ligand.Protein122990124743890Li S, Pei X, Zhang W, Xie HQ, Zhao B: Functional analysis of the dioxin response elements (DREs) of the murine CYP1A1 gene promoter: beyond the core DRE sequence. Int J Mol Sci. 2014 Apr 16;15(4):6475-87. doi: 10.3390/ijms15046475.64625Pathway22990226154658Ghotbaddini M, Powell JB: The AhR Ligand, TCDD, Regulates Androgen Receptor Activity Differently in Androgen-Sensitive versus Castration-Resistant Human Prostate Cancer Cells. Int J Environ Res Public Health. 2015 Jul 6;12(7):7506-18. doi: 10.3390/ijerph120707506.64625Pathway22990315328365Sun YV, Boverhof DR, Burgoon LD, Fielden MR, Zacharewski TR: Comparative analysis of dioxin response elements in human, mouse and rat genomic sequences. Nucleic Acids Res. 2004 Aug 24;32(15):4512-23. doi: 10.1093/nar/gkh782. Print 2004.64625Pathway229904H_acrPathway. (n.d.). Retrieved from https://cgap.nci.nih.gov/Pathways/BioCarta/h_acrPathway64625Pathway22990520945300Denison MS, Rogers JM, Rushing SR, Jones CL, Tetangco SC, Heath-Pagliuso S: Analysis of the aryl hydrocarbon receptor (AhR) signal transduction pathway. Curr Protoc Toxicol. 2002 May;Chapter 4:Unit4.8. doi: 10.1002/0471140856.tx0408s11.64625Pathway1CellCL:00000001Homo sapiens9606EukaryoteHuman12Mus musculus10090EukaryoteMouse17Rattus norvegicus10116EukaryoteRat5Bos taurus9913EukaryoteCattle5CytoplasmGO:000573715NucleusGO:00056348511PW_BS00000827151PW_BS0000273511512PW_BS0000284701517PW_BS000115435155PW_BS000115969832,3,7,8-tetrachlorodibenzo-p-dioxin2,3,7,8-Tetrachlorodibenzo-p-dioxin, also known as PCDD 48 or polychlorinated dibenzo p dioxins, belongs to the class of organic compounds known as chlorinated dibenzo-p-dioxins. These are organic compounds containing a chlorine atom attached to a dibenzo-p-dioxin moiety. 2,3,7,8-Tetrachlorodibenzo-p-dioxin exists as a solid and is considered to be practically insoluble (in water) and relatively neutral. 2,3,7,8-Tetrachlorodibenzo-p-dioxin is formally rated as a carcinogen (by IARC 1) and is also a potentially toxic compound. Dibenzodioxin derivatives that contain multiple chloride atoms bound to the benzene ring structures (PubChem).1746-01-615625[H]C1=C2OC3=C([H])C(Cl)=C(Cl)C([H])=C3OC2=C([H])C(Cl)=C1ClC12H4Cl4O2InChI=1S/C12H4Cl4O2/c13-5-1-9-10(2-6(5)14)18-12-4-8(16)7(15)3-11(12)17-9/h1-4HHGUFODBRKLSHSI-UHFFFAOYSA-N2,3,7,8-tetrachlorooxanthrene321.971319.8965402-5.940dioxin00TCDD;Chlorinated Dibenzo p dioxins;TetrachlorodibenzodioxinPW_C096983TCPDD8016288016827266Dioxin response elementDNAPW_NA000266DRE801992713267835113268447013269043514361Aryl hydrocarbon receptorP35869
Ligand-activated transcriptional activator. Binds to the XRE promoter region of genes it activates. Activates the expression of multiple phase I and II xenobiotic chemical metabolizing enzyme genes (such as the CYP1A1 gene). Mediates biochemical and toxic effects of halogenated aromatic hydrocarbons. Involved in cell-cycle regulation. Likely to play an important role in the development and maturation of many tissues. Regulates the circadian clock by inhibiting the basal and circadian expression of the core circadian component PER1. Inhibits PER1 by repressing the CLOCK-ARNTL/BMAL1 heterodimer mediated transcriptional activation of PER1.
AHR180158278016382103Heat shock protein HSP 90-alphaP07900Molecular chaperone. Has ATPase activityHMDBP02801HSP90AA114q32.33BC12106214378880157271650Aryl hydrocarbon receptorP35869Ligand-activated transcriptional activator. Binds to the XRE promoter region of genes it activates. Activates the expression of multiple phase I and II xenobiotic chemical metabolizing enzyme genes (such as the CYP1A1 gene). Mediates biochemical and toxic effects of halogenated aromatic hydrocarbons. Involved in cell-cycle regulation. Likely to play an important role in the development and maturation of many tissuesHMDBP01861AHR7p15U280631801658801692714360Aryl hydrocarbon receptor nuclear translocatorP27540
Required for activity of the Ah (dioxin) receptor. This protein is required for the ligand-binding subunit to translocate from the cytosol to the nucleus after ligand binding. The complex then initiates transcription of genes involved in the activation of PAH procarcinogens. The heterodimer with HIF1A or EPAS1/HIF2A functions as a transcriptional regulator of the adaptive response to hypoxia.
ARNT1801552714373Aryl hydrocarbon receptorP35869
Ligand-activated transcriptional activator. Binds to the XRE promoter region of genes it activates. Activates the expression of multiple phase I and II xenobiotic chemical metabolizing enzyme genes (such as the CYP1A1 gene). Mediates biochemical and toxic effects of halogenated aromatic hydrocarbons. Involved in cell-cycle regulation. Likely to play an important role in the development and maturation of many tissues. Regulates the circadian clock by inhibiting the basal and circadian expression of the core circadian component PER1. Inhibits PER1 by repressing the CLOCK-ARNTL/BMAL1 heterodimer mediated transcriptional activation of PER1.
AHR1801942780195814372Aryl hydrocarbon receptor nuclear translocatorP27540
Required for activity of the Ah (dioxin) receptor. This protein is required for the ligand-binding subunit to translocate from the cytosol to the nucleus after ligand binding. The complex then initiates transcription of genes involved in the activation of PAH procarcinogens. The heterodimer with HIF1A or EPAS1/HIF2A functions as a transcriptional regulator of the adaptive response to hypoxia.
ARNT180193277555Aryl hydrocarbon receptor1PW_P007555154311436180159271067Heat shock protein HSP 90-alpha1PW_P0010671222210327556AHR-complex-ligand1PW_P007556154321650154332103381650969838016187557AHR-ligand1PW_P0075571543416503916509698380166278016787554Aryl hydrocarbon receptor nuclear translocator1PW_P007554154301436080156277563AHR-ligand-ARNT1PW_P007563154431437315444143724014373969838019627110779truePW_R110779Right40303575551ProteinComplexfalse40303610671ProteinComplexfalse403037969831Compoundfalse40303875561ProteinComplexfalse110780truePW_R110780Right40303975561ProteinComplexfalse40304010671ProteinComplexfalse40304175571ProteinComplexfalse110782truePW_R110782Right40304475571ProteinComplexfalse40304575541ProteinComplexfalse40304675631ProteinComplexfalse377ActivationPW_I0003777537563ProteinComplex1754266NucleicAcid115880279698383false26320210regular10012015880289698383false55826210regular100120158802996983273false90343210regular100120158803396983273false113359710regular10012024382661227false103880214150nucleic_acidregular150705943601436182false2183828generegular15070594361210386false1985178generegular16080594362165082false4633528generegular15070594363210382false4684078generegular150705943642103276false8682228generegular160805943651650272false9383778generegular1507059437514360272false11383778generegular1507059437614373272false10385628generegular1507059437714372272false10036178generegular15070482579755564509859305559436048258010676450985930565943614825817556645098593057594362593058594363807715880282164643Modification4825821067645092759305959436448258375576450927593060594365807815880292164647Modification4825907554645092759307059437548259175636450927593071594376593072594377808215880332164659Modification2164640M363 262 C375 262 403 262 414 262 C414 362 413 385 414 412 5false182164641M363 412 C393 412 456 412 486 412 5false18trueM 554.0096189432334 563.5 L 567 556 L 554.0096189432334 548.5false2164642M358 557 C391 558 385 558 415 558 C415 532 415 428 414 398 5false18falsefalse2164643M553 342 L600 387 L555 386 z10false182164644M443 602 C413 602 398 602 368 602 5true18trueM 25.946855044164835 13.26155629629604 L 11 12 L 17.380887721185843 25.575134323078345false2164645M591 411 C668 410 888 410 938 412 5false18trueM 914.7202385063009 585.9748071421701 L 928 579 L 915.319759081534 570.9867927613433false2164646M868 262 C838 262 831 262 804 262 C804 289 804 368 804 411 5false18trueM 377.94685504416486 478.261556296296 L 363 477 L 369.38088772118584 490.5751343230783false2164647M1008 427 L952 427 L1009 479 z10false182164648M938 412 C862 410 766 626 716 625 5true18trueM 377.94685504416486 478.261556296296 L 363 477 L 369.38088772118584 490.5751343230783falsefalsefalse2164657M1013 447 C1013 477 1012 485 1013 510 C1036 510 1092 509 1112 509 C1112 529 1113 537 1113 562 5false182164658M1213 447 C1182 474 1092 575 1076 629 5true182164659M1128 592 L1128 642 L1178 592 z10false182164660M1113 562 C1112 526 1112 530 1112 509 C1133 509 1192 509 1213 509 C1213 485 1213 478 1213 447 5false18trueM 454.94685504416486 826.261556296296 L 440 825 L 446.38088772118584 838.5751343230784false2164666M1113 802 C1116 778 1070 917.5 1096 895.5 149true18trueM 25.946855044164835 731.261556296296 L 11 730 L 17.380887721185843 743.5751343230784false2164667M1113 674 C1113 704 1113 759 1113 802 149false18trueM 1294.1012710868117 839.526947995128 L 1295 854.5 L 1307.5176789518105 846.2351519276274false488662645091107798195842315880272164640Left105144825792164641Left105154825802164642Left105164825812164644Right4886636450911078027105174825812164645Left105184825822164646Right105194825832164648Right4886656450911078227105224825832164657Left105234825902164658Left105244825912164660Right15533776450927624382164666Right15434825912164667Left1591142936451.01.002143272671592179619071.91.9-9056678154329549M125 225 C125 175 175 125 225 125 C552 125 976 125 1303 125 C1353 125 1403 175 1403 225 C1403 428 1403 693 1403 896 C1403 946 1353 996 1303 996 C976 996 552 996 225 996 C175 996 125 946 125 896 C125 693 125 428 125 225 1true61278.0871.0330036M755 192 C756 249 752 861 754 915 93false61.0723.0245313235Transformation887305200.90.920015245314235Heterodimerization1118500200.90.920015245315235Translocation668401200.90.920015400821235Nucleus1103174201.01.020015400822235Cytoplasm423164191.01.020015155766563753728191132691939#FFF9C94598728