Aryl hydrocarbon receptor signaling (Homo sapiens)

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2, 9, 101, 2, 5, 8, 11...4, 7, 10332, 6nucleoplasmcytosolAHR:TCDD:2xHSP90AB1:AIP:PTGES3ARNT2 AHR PTGES3 ARNT TCDD AHR TCDD TCDDAHR:TCDDAIP AHR PTGES3 AHR:2xHSP90AB1:AIP:PTGES3HSP90AB1 AHR:TCDD:2xHSP90AB1:AIP:PTGES3ARNT 2xHSP90AB1:AIP:PTGES3HSP90AB1 ARNT2 ARNT, ARNT2HSP90AB1 AHR:TCDD:ARNTAIP PTGES3 PTGES3 TCDD AHR AIP AIP AHRR AHR ARNT ARNT2 AHRR:ARNTAHRRTCDD HSP90AB1


Description

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that belongs to the basic helix-loop-helix/PER-ARNT-SIM family of DNA binding proteins and controls the expression of a diverse set of genes. Two major types of environmental compounds can activate AHR signaling: halogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and polycyclic aromatic hydrocarbons (PAH) such as benzo(a)pyrene. Unliganded AHR forms a complex in the cytosol with two copies of 90kD heat shock protein (HSP90AB1), one X-associated protein (AIP), and one p23 molecular chaperone protein (PTGES3). After ligand binding and activation, the AHR complex translocates to the nucleus, disassociates from the chaperone subunits, dimerises with the aryl hydrocarbon receptor nuclear translocator (ARNT) and transactivates target genes via binding to xenobiotic response elements (XREs) in their promoter regions. AHR targets genes of Phase I and Phase II metabolism, such as cytochrome P450 1A1 (CYP1A1), cytochorme P450 1B1 (CYP1B1), NAD(P)H:quinone oxidoreductase I (NQO1) and aldehyde dehydrogenase 3 (ALHD3A1). This is thought to be an organism's response to foreign chemical exposure and normally, foreign chemicals are made less reactive by the induction and therefore increased activity of these enzymes (Beischlag et al. 2008).

AHR itself is regulated by the aryl hydrocarbon receptor repressor (AHRR, aka BHLHE77, KIAA1234), an evolutionarily conserved bHLH-PAS protein that inhibits both xenobiotic-induced and constitutively active AHR transcriptional activity in many species. AHRR resides predominantly in the nuclear compartment where it competes with AHR for binding to ARNT. As a result, there is competition between AHR:ARNT and AHRR:ARNT complexes for binding to XREs in target genes and AHRR can repress the transcription activity of AHR (Hahn et al. 2009, Haarmann-Stemmann & Abel 2006). View original pathway at Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 8937144
Reactome-version 
Reactome version: 74
Reactome Author 
Reactome Author: Jassal, Bijay

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Bibliography

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  1. Beischlag TV, Luis Morales J, Hollingshead BD, Perdew GH.; ''The aryl hydrocarbon receptor complex and the control of gene expression.''; PubMed Europe PMC Scholia
  2. Nguyen PM, Wang D, Wang Y, Li Y, Uchizono JA, Chan WK.; ''p23 co-chaperone protects the aryl hydrocarbon receptor from degradation in mouse and human cell lines.''; PubMed Europe PMC Scholia
  3. Ema M, Ohe N, Suzuki M, Mimura J, Sogawa K, Ikawa S, Fujii-Kuriyama Y.; ''Dioxin binding activities of polymorphic forms of mouse and human arylhydrocarbon receptors.''; PubMed Europe PMC Scholia
  4. Lees MJ, Whitelaw ML.; ''Multiple roles of ligand in transforming the dioxin receptor to an active basic helix-loop-helix/PAS transcription factor complex with the nuclear protein Arnt.''; PubMed Europe PMC Scholia
  5. Forsythe HL, Jarvis JL, Turner JW, Elmore LW, Holt SE.; ''Stable association of hsp90 and p23, but Not hsp70, with active human telomerase.''; PubMed Europe PMC Scholia
  6. Kazlauskas A, Sundström S, Poellinger L, Pongratz I.; ''The hsp90 chaperone complex regulates intracellular localization of the dioxin receptor.''; PubMed Europe PMC Scholia
  7. Mimura J, Fujii-Kuriyama Y.; ''Functional role of AhR in the expression of toxic effects by TCDD.''; PubMed Europe PMC Scholia
  8. Kanno Y, Miyama Y, Takane Y, Nakahama T, Inouye Y.; ''Identification of intracellular localization signals and of mechanisms underlining the nucleocytoplasmic shuttling of human aryl hydrocarbon receptor repressor.''; PubMed Europe PMC Scholia
  9. Meyer BK, Pray-Grant MG, Vanden Heuvel JP, Perdew GH.; ''Hepatitis B virus X-associated protein 2 is a subunit of the unliganded aryl hydrocarbon receptor core complex and exhibits transcriptional enhancer activity.''; PubMed Europe PMC Scholia
  10. Hahn ME, Allan LL, Sherr DH.; ''Regulation of constitutive and inducible AHR signaling: complex interactions involving the AHR repressor.''; PubMed Europe PMC Scholia
  11. Haarmann-Stemmann T, Abel J.; ''The arylhydrocarbon receptor repressor (AhRR): structure, expression, and function.''; PubMed Europe PMC Scholia
  12. Evans BR, Karchner SI, Allan LL, Pollenz RS, Tanguay RL, Jenny MJ, Sherr DH, Hahn ME.; ''Repression of aryl hydrocarbon receptor (AHR) signaling by AHR repressor: role of DNA binding and competition for AHR nuclear translocator.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
116424view09:11, 7 May 2021EweitzModified title
114803view16:30, 25 January 2021ReactomeTeamReactome version 75
113247view11:31, 2 November 2020ReactomeTeamReactome version 74
112465view15:41, 9 October 2020ReactomeTeamReactome version 73
101374view11:26, 1 November 2018ReactomeTeamreactome version 66
100912view21:01, 31 October 2018ReactomeTeamreactome version 65
100453view19:36, 31 October 2018ReactomeTeamreactome version 64
100000view16:19, 31 October 2018ReactomeTeamreactome version 63
99554view14:53, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
93572view11:27, 9 August 2017ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
2xHSP90AB1:AIP:PTGES3ComplexR-HSA-8937201 (Reactome)
AHR ProteinP35869 (Uniprot-TrEMBL)
AHR:2xHSP90AB1:AIP:PTGES3ComplexR-HSA-8936844 (Reactome)
AHR:TCDD:2xHSP90AB1:AIP:PTGES3ComplexR-HSA-8936846 (Reactome)
AHR:TCDD:2xHSP90AB1:AIP:PTGES3ComplexR-HSA-8937154 (Reactome)
AHR:TCDD:ARNTComplexR-HSA-8937203 (Reactome)
AHR:TCDDComplexR-HSA-8937150 (Reactome)
AHRR ProteinA9YTQ3 (Uniprot-TrEMBL)
AHRR:ARNTComplexR-HSA-8936835 (Reactome)
AHRRProteinA9YTQ3 (Uniprot-TrEMBL)
AIP ProteinO00170 (Uniprot-TrEMBL)
ARNT ProteinP27540 (Uniprot-TrEMBL)
ARNT, ARNT2ComplexR-HSA-8936837 (Reactome)
ARNT2 ProteinQ9HBZ2 (Uniprot-TrEMBL)
HSP90AB1 ProteinP08238 (Uniprot-TrEMBL)
PTGES3 ProteinQ15185 (Uniprot-TrEMBL)
TCDD MetaboliteCHEBI:28119 (ChEBI)
TCDDMetaboliteCHEBI:28119 (ChEBI)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
2xHSP90AB1:AIP:PTGES3ArrowR-HSA-8937191 (Reactome)
AHR:2xHSP90AB1:AIP:PTGES3R-HSA-8936849 (Reactome)
AHR:TCDD:2xHSP90AB1:AIP:PTGES3ArrowR-HSA-8936849 (Reactome)
AHR:TCDD:2xHSP90AB1:AIP:PTGES3ArrowR-HSA-8937169 (Reactome)
AHR:TCDD:2xHSP90AB1:AIP:PTGES3R-HSA-8937169 (Reactome)
AHR:TCDD:2xHSP90AB1:AIP:PTGES3R-HSA-8937191 (Reactome)
AHR:TCDD:ARNTArrowR-HSA-8937177 (Reactome)
AHR:TCDDArrowR-HSA-8937191 (Reactome)
AHR:TCDDR-HSA-8937177 (Reactome)
AHRR:ARNTArrowR-HSA-8936851 (Reactome)
AHRRR-HSA-8936851 (Reactome)
ARNT, ARNT2R-HSA-8936851 (Reactome)
ARNT, ARNT2R-HSA-8937177 (Reactome)
R-HSA-8936849 (Reactome) The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor that can control the expression of a diverse set of genes. Two major types of environmental compounds can activate AHR signaling: halogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and polycyclic aromatic hydrocarbons (PAH) such as benzo(a)pyrene. Unliganded AHR forms a complex in the cytosol with two copies of 90kD heat shock protein (HSP90AB1) (Forsythe et al. 2001), one X-associated protein (AIP) (Meyer et al. 1998), and one p23 molecular chaperone protein (PTGES3) (Nguyen et al. 2012, Beischlag et al. 2008). Here, the binding of TCDD is shown.
R-HSA-8936851 (Reactome) The aryl hydrocarbon receptor repressor (AHRR) is predominantly localised in the nucleus of cells (Kanno et al. 2007) and can bind AHR nuclear translocator (ARNT). The resultant AHRR:ARNT complex can compete with AHR:ARNT for binding to the xenobiotic response element (XRE) on target genes such CYP1A1 (Evans et al. 2008, Hahn et al. 2009).
R-HSA-8937169 (Reactome) After ligand binding and activation, the AHR complex translocates to the nucleus by an unknown mechanism (Beischlag et al. 2008) but it has been hypothesised that ligand binding to AHR promoted p23-associated hsp90 complex-mediated interaction of AHR with the nuclear import receptor protein pendulin and subsequent nuclear translocation of the receptor (Kazlauskas et al. 2001).
R-HSA-8937177 (Reactome) Ligand-bound aryl hydrocarbon receptor (AHR:TCDD) disassociates from the chaperone subunits to then dimerise with the aryl hydrocarbon receptor nuclear translocator (ARNT) (Lees & Whitelaw 1999).
R-HSA-8937191 (Reactome) After ligand binding and activation, the AHR complex translocates to the nucleus where it disassociates from the chaperone subunits to then dimerise with the aryl hydrocarbon receptor nuclear translocator (ARNT) (Lees & Whitelaw 1999).
TCDDR-HSA-8936849 (Reactome)
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