Aryl hydrocarbon receptor pathway (Homo sapiens)

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30, 4548813205218, 50, 532, 351095231, 551324133STAT111CyNuActivationTCDD30CyNuNEDD8SUMO7CyNuCyNuProteinProteinNucleusHSP90AA1RETEP300TCDDAIPCYP1A1DRE regionPAHZAC1NQO1CCL1KLF6Proliferation and tumorigenesis NFE2L2EGFRXRECDKN1BCalcium channelARNTESR1VEGFApRbEBNA-326, 3334021, 445, 8, 56AIP1437, 43P19133912, 30, 4528, 50, 51L3657AHRP237, 54AHRAHRHSP90AA13017, 46HSP90AA119MYC22TATAEGFR pathwayTNF18CDC37SRC2RAF1PPMAP2K1PMAPK1PTGS210PSRC1RELANFKB1RELANFKB1EP30016PSRC1AngiogenesisNCOA7NRIP1CYP1A1CD36LPLNFE2L247FGF21HPGDSGCLCOxidative stressNRIP1NF1NCOA727NCOR2CYP1A23849CYP1B1Estrogen metabolism24, 29Enzyme ComplexProteinReceptorLigandmRNASmall moleculeInduced activationInhibitionAuto catalysisTransportPositive regulation of gene expressionLeads to through unknown mechanismNegative regulation of gene expressionTranslocation UbiquitinationDeubiquitinationSumoylationInduced catalysisProtein-protein interactionAcetylationDephosphorylationLEGENDPhosphorylationDeacetylationGolgi apparatusEndosomeNucleusMitochondrionDesumoylationMethylationDemethylationPalmitoylationCytoplasmECPlasma membraneMTEndoplasmic reticulumCYPMGONUExtracellularERENProteolytic cleavageMoleculeCDKN1ACDK26, 34RB1E2F1Cell cycle inhibitionDetoxification and metabolism of xenobioticsCell survivalAHRREP30015FAS / FAS-L (Apoptosis)NRASHRASKRASTCDD5, 8, 56PAH21, 44Cell survival42Modulation of estrogen receptor signalingHSP90AA154


The Aryl Hydrocarbon receptor (AhR) is ligand activated transcription factor that regulates wide spectrum of gene expression. The main mediator of AhR is 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) or polycyclic aromatic hydrocarbons which are widespread environmental pollutant causing a variety of severe health effects, e.g. immunosuppression, carcinogenesis and hepatotoxicity.

AhR is a member of basic helix-loop-helix-Per-Arnt-Sim (bHLH-PAS) superfamily of transcription factors. In the absence of ligand, the AhR can be found in the cytosol, bound to a dimer of the heat shock protein of 90 kDa (Hsp90) and the immunophilin-like protein, AIP (also known as XAP2 and ARA9). Upon ligand binding, the AHR translocates to the nucleus and binds with ARNT. The AHR/ARNT heterodimer binds to xenobiotic response elements and regulates a diverse set of genes.

Proteins on this pathway have targeted assays available via the CPTAC Assay Portal

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  1. Kashuba E, Kashuba V, Pokrovskaja K, Klein G, Szekely L; ''Epstein-Barr virus encoded nuclear protein EBNA-3 binds XAP-2, a protein associated with Hepatitis B virus X antigen.''; Oncogene, 2000 PubMed Europe PMC Scholia
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  4. Lu H, Cui W, Klaassen CD; ''Nrf2 protects against 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced oxidative injury and steatohepatitis.''; Toxicol Appl Pharmacol, 2011 PubMed Europe PMC Scholia
  5. Poland A, Glover E, Kende AS; ''Stereospecific, high affinity binding of 2,3,7,8-tetrachlorodibenzo-p-dioxin by hepatic cytosol. Evidence that the binding species is receptor for induction of aryl hydrocarbon hydroxylase.''; J Biol Chem, 1976 PubMed Europe PMC Scholia
  6. Coats S, Whyte P, Fero ML, Lacy S, Chung G, Randel E, Firpo E, Roberts JM; ''A new pathway for mitogen-dependent cdk2 regulation uncovered in p27(Kip1)-deficient cells.''; Curr Biol, 1999 PubMed Europe PMC Scholia
  7. Kazlauskas A, Poellinger L, Pongratz I; ''Evidence that the co-chaperone p23 regulates ligand responsiveness of the dioxin (Aryl hydrocarbon) receptor.''; J Biol Chem, 1999 PubMed Europe PMC Scholia
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  11. Kimura A, Naka T, Nohara K, Fujii-Kuriyama Y, Kishimoto T; ''Aryl hydrocarbon receptor regulates Stat1 activation and participates in the development of Th17 cells.''; Proc Natl Acad Sci U S A, 2008 PubMed Europe PMC Scholia
  12. Takahata S, Sogawa K, Kobayashi A, Ema M, Mimura J, Ozaki N, Fujii-Kuriyama Y; ''Transcriptionally active heterodimer formation of an Arnt-like PAS protein, Arnt3, with HIF-1a, HLF, and clock.''; Biochem Biophys Res Commun, 1998 PubMed Europe PMC Scholia
  13. Vargiolu M, Fusco D, Kurelac I, Dirnberger D, Baumeister R, Morra I, Melcarne A, Rimondini R, Romeo G, Bonora E; ''The tyrosine kinase receptor RET interacts in vivo with aryl hydrocarbon receptor-interacting protein to alter survivin availability.''; J Clin Endocrinol Metab, 2009 PubMed Europe PMC Scholia
  14. Monteiro P, Gilot D, Le Ferrec E, Rauch C, Lagadic-Gossmann D, Fardel O; ''Dioxin-mediated up-regulation of aryl hydrocarbon receptor target genes is dependent on the calcium/calmodulin/CaMKIalpha pathway.''; Mol Pharmacol, 2008 PubMed Europe PMC Scholia
  15. Umannovأ، L, Machala M, Topinka J, Novأ،kovأ، Z, Milcovأ، A, Kozubأ­k A, Vondrأ،cek J; ''Tumor necrosis factor-alpha potentiates genotoxic effects of benzo[a]pyrene in rat liver epithelial cells through upregulation of cytochrome P450 1B1 expression.''; Mutat Res, 2008 PubMed Europe PMC Scholia
  16. Sutter CH, Yin H, Li Y, Mammen JS, Bodreddigari S, Stevens G, Cole JA, Sutter TR; ''EGF receptor signaling blocks aryl hydrocarbon receptor-mediated transcription and cell differentiation in human epidermal keratinocytes.''; Proc Natl Acad Sci U S A, 2009 PubMed Europe PMC Scholia
  17. Kekatpure VD, Dannenberg AJ, Subbaramaiah K; ''HDAC6 modulates Hsp90 chaperone activity and regulates activation of aryl hydrocarbon receptor signaling.''; J Biol Chem, 2009 PubMed Europe PMC Scholia
  18. Cheon H, Woo YS, Lee JY, Kim HS, Kim HJ, Cho S, Won NH, Sohn J; ''Signaling pathway for 2,3,7,8-tetrachlorodibenzo-p-dioxin-induced TNF-alpha production in differentiated THP-1 human macrophages.''; Exp Mol Med, 2007 PubMed Europe PMC Scholia
  19. Perdew GH; ''Association of the Ah receptor with the 90-kDa heat shock protein.''; J Biol Chem, 1988 PubMed Europe PMC Scholia
  20. Shin S, Wakabayashi N, Misra V, Biswal S, Lee GH, Agoston ES, Yamamoto M, Kensler TW; ''NRF2 modulates aryl hydrocarbon receptor signaling: influence on adipogenesis.''; Mol Cell Biol, 2007 PubMed Europe PMC Scholia
  21. Billiard SM, Hahn ME, Franks DG, Peterson RE, Bols NC, Hodson PV; ''Binding of polycyclic aromatic hydrocarbons (PAHs) to teleost aryl hydrocarbon receptors (AHRs).''; Comp Biochem Physiol B Biochem Mol Biol, 2002 PubMed Europe PMC Scholia
  22. Kim DW, Gazourian L, Quadri SA, Romieu-Mourez R, Sherr DH, Sonenshein GE; ''The RelA NF-kappaB subunit and the aryl hydrocarbon receptor (AhR) cooperate to transactivate the c-myc promoter in mammary cells.''; Oncogene, 2000 PubMed Europe PMC Scholia
  23. Mayati A, Levoin N, Paris H, N'Diaye M, Courtois A, Uriac P, Lagadic-Gossmann D, Fardel O, Le Ferrec E; ''Induction of intracellular calcium concentration by environmental benzo(a)pyrene involves a خ²2-adrenergic receptor/adenylyl cyclase/Epac-1/inositol 1,4,5-trisphosphate pathway in endothelial cells.''; J Biol Chem, 2012 PubMed Europe PMC Scholia
  24. Shimada T, Oda Y, Gillam EM, Guengerich FP, Inoue K; ''Metabolic activation of polycyclic aromatic hydrocarbons and other procarcinogens by cytochromes P450 1A1 and P450 1B1 allelic variants and other human cytochromes P450 in Salmonella typhimurium NM2009.''; Drug Metab Dispos, 2001 PubMed Europe PMC Scholia
  25. Park S, Dong B, Matsumura F; ''Rapid activation of c-Src kinase by dioxin is mediated by the Cdc37-HSP90 complex as part of Ah receptor signaling in MCF10A cells.''; Biochemistry, 2007 PubMed Europe PMC Scholia
  26. Elferink CJ, Ge NL, Levine A; ''Maximal aryl hydrocarbon receptor activity depends on an interaction with the retinoblastoma protein.''; Mol Pharmacol, 2001 PubMed Europe PMC Scholia
  27. Nguyen TA, Hoivik D, Lee JE, Safe S; ''Interactions of nuclear receptor coactivator/corepressor proteins with the aryl hydrocarbon receptor complex.''; Arch Biochem Biophys, 1999 PubMed Europe PMC Scholia
  28. Riese DJ 2nd, Stern DF; ''Specificity within the EGF family/ErbB receptor family signaling network.''; Bioessays, 1998 PubMed Europe PMC Scholia
  29. Tang YM, Wo YY, Stewart J, Hawkins AL, Griffin CA, Sutter TR, Greenlee WF; ''Isolation and characterization of the human cytochrome P450 CYP1B1 gene.''; J Biol Chem, 1996 PubMed Europe PMC Scholia
  30. Lo R, Matthews J; ''High-resolution genome-wide mapping of AHR and ARNT binding sites by ChIP-Seq.''; Toxicol Sci, 2012 PubMed Europe PMC Scholia
  31. Xu S, Weerachayaphorn J, Cai SY, Soroka CJ, Boyer JL; ''Aryl hydrocarbon receptor and NF-E2-related factor 2 are key regulators of human MRP4 expression.''; Am J Physiol Gastrointest Liver Physiol, 2010 PubMed Europe PMC Scholia
  32. Gottifredi V, McKinney K, Poyurovsky MV, Prives C; ''Decreased p21 levels are required for efficient restart of DNA synthesis after S phase block.''; J Biol Chem, 2004 PubMed Europe PMC Scholia
  33. Ge NL, Elferink CJ; ''A direct interaction between the aryl hydrocarbon receptor and retinoblastoma protein. Linking dioxin signaling to the cell cycle.''; J Biol Chem, 1998 PubMed Europe PMC Scholia
  34. Kwon TK, Nordin AA; ''Identification of cdk2 binding sites on the p27Kip1 cyclin-dependent kinase inhibitor.''; Oncogene, 1998 PubMed Europe PMC Scholia
  35. Enan E, Matsumura F; ''Identification of c-Src as the integral component of the cytosolic Ah receptor complex, transducing the signal of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) through the protein phosphorylation pathway.''; Biochem Pharmacol, 1996 PubMed Europe PMC Scholia
  36. Chahal HS, Trivellin G, Leontiou CA, Alband N, Fowkes RC, Tahir A, Igreja SC, Chapple JP, Jordan S, Lupp A, Schulz S, Ansorge O, Karavitaki N, Carlsen E, Wass JA, Grossman AB, Korbonits M; ''Somatostatin analogs modulate AIP in somatotroph adenomas: the role of the ZAC1 pathway.''; J Clin Endocrinol Metab, 2012 PubMed Europe PMC Scholia
  37. Ahmed S, Valen E, Sandelin A, Matthews J; ''Dioxin increases the interaction between aryl hydrocarbon receptor and estrogen receptor alpha at human promoters.''; Toxicol Sci, 2009 PubMed Europe PMC Scholia
  38. Beischlag TV, Perdew GH; ''ER alpha-AHR-ARNT protein-protein interactions mediate estradiol-dependent transrepression of dioxin-inducible gene transcription.''; J Biol Chem, 2005 PubMed Europe PMC Scholia
  39. Kolluri SK, Weiss C, Koff A, Gأ¶ttlicher M; ''p27(Kip1) induction and inhibition of proliferation by the intracellular Ah receptor in developing thymus and hepatoma cells.''; Genes Dev, 1999 PubMed Europe PMC Scholia
  40. Nebert DW, Petersen DD, Puga A; ''Human AH locus polymorphism and cancer: inducibility of CYP1A1 and other genes by combustion products and dioxin.''; Pharmacogenetics, 1991 PubMed Europe PMC Scholia
  41. Ke S, Rabson AB, Germino JF, Gallo MA, Tian Y; ''Mechanism of suppression of cytochrome P-450 1A1 expression by tumor necrosis factor-alpha and lipopolysaccharide.''; J Biol Chem, 2001 PubMed Europe PMC Scholia
  42. Muntanأ©-Relat J, Ourlin JC, Domergue J, Maurel P; ''Differential effects of cytokines on the inducible expression of CYP1A1, CYP1A2, and CYP3A4 in human hepatocytes in primary culture.''; Hepatology, 1995 PubMed Europe PMC Scholia
  43. Klinge CM, Kaur K, Swanson HI; ''The aryl hydrocarbon receptor interacts with estrogen receptor alpha and orphan receptors COUP-TFI and ERRalpha1.''; Arch Biochem Biophys, 2000 PubMed Europe PMC Scholia
  44. Trombino AF, Near RI, Matulka RA, Yang S, Hafer LJ, Toselli PA, Kim DW, Rogers AE, Sonenshein GE, Sherr DH; ''Expression of the aryl hydrocarbon receptor/transcription factor (AhR) and AhR-regulated CYP1 gene transcripts in a rat model of mammary tumorigenesis.''; Breast Cancer Res Treat, 2000 PubMed Europe PMC Scholia
  45. Probst MR, Reisz-Porszasz S, Agbunag RV, Ong MS, Hankinson O; ''Role of the aryl hydrocarbon receptor nuclear translocator protein in aryl hydrocarbon (dioxin) receptor action.''; Mol Pharmacol, 1993 PubMed Europe PMC Scholia
  46. Soshilov A, Denison MS; ''Ligand displaces heat shock protein 90 from overlapping binding sites within the aryl hydrocarbon receptor ligand-binding domain.''; J Biol Chem, 2011 PubMed Europe PMC Scholia
  47. Minami K, Nakajima M, Fujiki Y, Katoh M, Gonzalez FJ, Yokoi T; ''Regulation of insulin-like growth factor binding protein-1 and lipoprotein lipase by the aryl hydrocarbon receptor.''; J Toxicol Sci, 2008 PubMed Europe PMC Scholia
  48. Bell DR, Poland A; ''Binding of aryl hydrocarbon receptor (AhR) to AhR-interacting protein. The role of hsp90.''; J Biol Chem, 2000 PubMed Europe PMC Scholia
  49. Quattrochi LC, Vu T, Tukey RH; ''The human CYP1A2 gene and induction by 3-methylcholanthrene. A region of DNA that supports AH-receptor binding and promoter-specific induction.''; J Biol Chem, 1994 PubMed Europe PMC Scholia
  50. Madhukar BV, Brewster DW, Matsumura F; ''Effects of in vivo-administered 2,3,7,8-tetrachlorodibenzo-p-dioxin on receptor binding of epidermal growth factor in the hepatic plasma membrane of rat, guinea pig, mouse, and hamster.''; Proc Natl Acad Sci U S A, 1984 PubMed Europe PMC Scholia
  51. Madhukar BV, Ebner K, Matsumura F, Bombick DW, Brewster DW, Kawamoto T; ''2,3,7,8-Tetrachlorodibenzo-p-dioxin causes an increase in protein kinases associated with epidermal growth factor receptor in the hepatic plasma membrane.''; J Biochem Toxicol, 1988 PubMed Europe PMC Scholia
  52. Singh NP, Nagarkatti M, Nagarkatti PS; ''Role of dioxin response element and nuclear factor-kappaB motifs in 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated regulation of Fas and Fas ligand expression.''; Mol Pharmacol, 2007 PubMed Europe PMC Scholia
  53. Biscardi JS, Maa MC, Tice DA, Cox ME, Leu TH, Parsons SJ; ''c-Src-mediated phosphorylation of the epidermal growth factor receptor on Tyr845 and Tyr1101 is associated with modulation of receptor function.''; J Biol Chem, 1999 PubMed Europe PMC Scholia
  54. Hollingshead BD, Petrulis JR, Perdew GH; ''The aryl hydrocarbon (Ah) receptor transcriptional regulator hepatitis B virus X-associated protein 2 antagonizes p23 binding to Ah receptor-Hsp90 complexes and is dispensable for receptor function.''; J Biol Chem, 2004 PubMed Europe PMC Scholia
  55. Miao W, Hu L, Scrivens PJ, Batist G; ''Transcriptional regulation of NF-E2 p45-related factor (NRF2) expression by the aryl hydrocarbon receptor-xenobiotic response element signaling pathway: direct cross-talk between phase I and II drug-metabolizing enzymes.''; J Biol Chem, 2005 PubMed Europe PMC Scholia
  56. Landi MT, Bertazzi PA, Baccarelli A, Consonni D, Masten S, Lucier G, Mocarelli P, Needham L, Caporaso N, Grassman J; ''TCDD-mediated alterations in the AhR-dependent pathway in Seveso, Italy, 20 years after the accident.''; Carcinogenesis, 2003 PubMed Europe PMC Scholia
  57. Roman AC, Carvajal-Gonzalez JM, Rico-Leo EM, Fernandez-Salguero PM; ''Dioxin receptor deficiency impairs angiogenesis by a mechanism involving VEGF-A depletion in the endothelium and transforming growth factor-beta overexpression in the stroma.''; J Biol Chem, 2009 PubMed Europe PMC Scholia


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External references


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NameTypeDatabase referenceComment
AHRGeneProduct196 (Entrez Gene)
AHRRGeneProduct57491 (Entrez Gene)
AIPGeneProductENSG00000110711 (Ensembl)
ARNTGeneProduct405 (Entrez Gene)
AngiogenesisPathwayWP1539 (WikiPathways)
CCL1GeneProduct6346 (Entrez Gene) PMID: 16679317 PAHs induce expression of the chemokine CCL1 in an AhR- and calcium-dependent manner.
CD36GeneProduct948 (Entrez Gene)
CDC37GeneProduct11140 (Entrez Gene)
CDK2GeneProduct1017 (Entrez Gene)
CDKN1AGeneProduct1026 (Entrez Gene)
CDKN1BGeneProduct1027 (Entrez Gene)
CYP1A1Protein1543 (Entrez Gene)
CYP1A2GeneProduct1544 (Entrez Gene)
CYP1B1GeneProduct1545 (Entrez Gene)
Calcium channel
Cell cycle inhibitionPathway
Cell survivalPathway
Cell survival Pathway
DRE regionComplex
Detoxification and metabolism of xenobiotics Pathway
E2F1GeneProduct1869 (Entrez Gene)
EBNA-3Protein17494212 (Entrez Gene)
EGFR pathwayPathwayWP1910 (WikiPathways)
EGFRGeneProduct1956 (Entrez Gene)
EP300Protein2033 (Entrez Gene)
ESR1Protein2099 (Entrez Gene) Estrogen Receptor
Estrogen metabolismPathwayWP697 (WikiPathways)
FAS / FAS-L (Apoptosis)PathwayWP254 (WikiPathways)
FGF21Protein26291 (Entrez Gene)
GCLCProtein2729 (Entrez Gene)
HPGDSProtein27306 (Entrez Gene)
HRASGeneProductENSG00000174775 (Ensembl)
HSP90AA1GeneProduct3320 (Entrez Gene)
KLF6GeneProduct1316 (Entrez Gene)
KRASGeneProductENSG00000133703 (Ensembl)
LPLProtein4023 (Entrez Gene) lipoprotein lipase
MAP2K1GeneProductENSG00000169032 (Ensembl)
MAPK1Protein5594 (Entrez Gene)
MYCProtein4609 (Entrez Gene)
Modulation of estrogen receptor signalingPathwayWP712 (WikiPathways)
NCOA7Protein135112 (Entrez Gene)
NCOR2Protein9612 (Entrez Gene)
NF1Protein4763 (Entrez Gene)
NFE2L2GeneProduct4780 (Entrez Gene)
NFKB1GeneProduct4790 (Entrez Gene)
NQO1Protein1728 (Entrez Gene)
NRASGeneProductENSG00000213281 (Ensembl)
NRIP1Protein8204 (Entrez Gene)
Oxidative stress PathwayWP408 (WikiPathways)
P23GeneProductENSG00000110711 (Ensembl)
PAHMetaboliteCHEBI:33848 (ChEBI)
PSRC1GeneProduct84722 (Entrez Gene)
PTGS2GeneProduct5743 (Entrez Gene)
Proliferation and tumorigenesis Pathway
RAF1GeneProductENSG00000132155 (Ensembl)
RB1GeneProduct5925 (Entrez Gene)
RELAGeneProduct5970 (Entrez Gene)
RETProtein5979 (Entrez Gene)
SRCProtein6714 (Entrez Gene)
TCDDMetaboliteCHEBI:28119 (ChEBI)
TNFGeneProduct7124 (Entrez Gene)
VEGFAGeneProduct7422 (Entrez Gene)
XRExenobiotic responsive element
ZAC1Protein5325 (Entrez Gene)
pRbProteinP06400 (Uniprot-TrEMBL)

Annotated Interactions

No annotated interactions

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