Regulation of Hypoxia-inducible Factor (HIF) by oxygen (Homo sapiens)

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4, 5, 10, 35, 38...22, 49, 5624, 62, 6644, 50, 5218, 22, 32, 561221, 42, 43, 50, 6414, 16, 22, 23, 31...11, 20, 259, 11, 17, 20, 46...7, 18, 22, 32, 569, 11, 20, 46, 49...19, 39, 41, 55, 6430, 576, 27, 36, 51, 52, 62...20, 40, 46, 487, 22, 49, 567, 14, 16, 22, 23, 31...2, 8, 22, 3713, 15, 20, 33, 40...13, 15, 17, 40, 46...nucleoplasmcytosolmitochondrial inner membraneVHL:EloB,C:CUL2:RBX1UBC(229-304) CUL2 WTIP PSMD3 RBX1 CREBBPHP-HIF3A ub-HIF-alpha:VHL:EloB,C:CUL2:RBX1PSMC1 EGLN3 UBC(533-608) PSMB6 SUCCAUBC(77-152) UBA52(1-76) UBB(77-152) CUL2 CO2PSMD1 UBE2D1,2,3:UbiquitinTCEB2 UBC(381-456) PSMA2 RBX1 ub-hydroxyPro-HIF-alpha:VHL:EloB:EloC:CUL2:RBX1UBC(153-228) VEGFA geneUBC(153-228) UBB(153-228) UBE2D2 hydroxyAsn-HIF1A,HIF2AhydroxyPro-HIF-alphaPSMA1 2xHP-EPAS1 CO2RBX1 UBE2D1 UBE2D2 UBE2D3 UBC(305-380) RPS27A(1-76) UBC(457-532) HP-HIF3A ELOB PSMD6 UBC(533-608) UBB(77-152) 2xHP-HIF1AHP-HIF3A TCEB1 HIF1APSMC3 EPAS1 PSMD11 FIH1:FIH1PSMD12 PHD2,3:LIMD1,AJUBA,WTIP:VHL:EloB:EloC:CUL2:RBX1LIMD1 ELOB hydroxyPro-HIF-alphaUBC(229-304) O2UBE2D1 ELOC LIMD1 UBC(305-380) UBB(77-152) UBA52(1-76) UBA52(1-76) UBC(533-608) HIF1AEPAS1 HP-HIF3A EP300LIMD1 HP-HIF3AUBC(533-608) O2UBE2D1,2,3UBC(457-532) CO2CITED22xHP-HIF1A VHL UBC(1-76) UBC(305-380) SUCCALIMD1 UBC(229-304) EPO genePSMC5 HIFUBC(381-456) UBC(533-608) HIF3A EGLN3 AJUBA EGLN1 UBC(381-456) UBE2D2 HIGD1A2xHP-HIF1A PSMB5 UBC(1-76) CREBBP UBE2D3 UBB(77-152) VHL 2xHP-EPAS1 UBE2D1,2,3PSMA7 HIF3A VHL PSMD4 EPAS1 VHL HIF-alphaEPAS1HIF1A,HIF2AVEGFAEGLN3 HP-HIF3A SHFM1 EGLN1 EGLN3 HP-HIF3A ELOC CUL2 HIF3AUBB(153-228) HIGD1A geneUBB(1-76) UBA52(1-76) ELOB PSME3 CA9EGLN1 ELOC 2xHP-HIF1A 2xHP-EPAS1 2xHP-EPAS1 2xHP-EPAS1CUL2 PSMB2 PSMD2 UBC(533-608) UBB(1-76) UBC(229-304) PSMB11 PSMC6 UBA52(1-76) ub-hydroxyPro-HIF-alpha:VCB (with or without LIMD1)UBC(457-532) PSMA8 CUL2 TCEB1 UBC(457-532) HIF1A 2xHP-EPAS1 HP-HIF3A PHD1,3PSMB9 UBC(229-304) PSMB8 ELOB VBC complex (with orwithout LIMD1)ARNT UBE2D2 HIF:CBP:p300UBC(305-380) PSMB4 RBX1 UBE2D1 PSMB10 UBC(305-380) PSMF1 PSMD14 UBB(77-152) EPAS1PSMB3 UBC(1-76) UBC(305-380) ub-hydroxyPro-HIF-alpha:VHL:EloB:EloC:CUL2:RBX1:LIMD1,AJUBA,WTIF:PHD2,3RBX1 2xHP-HIF1APSMA6 PSMA4 HIF1A UBC(77-152) 2xHP-HIF1A UBC(153-228) VHL HP-HIF3AUBC(77-152) UBC(609-684) VHL UBC(381-456) ELOC PSME1 TCEB2 PSMD10 CA9 gene2xHP-HIF1A PSMB1 VHL UBC(1-76) UBC(609-684) UBE2D1 RBX1 WTIP HP-HIF3A HIF1AN EPOUbUBB(1-76) UBA52(1-76) WTIP RBX1 CUL2 CUL2 HIF1A HN-EPAS1 UBC(153-228) UBC(77-152) DNA UBC(457-532) 2OG2xHP-EPAS1HN-HIF1A VHL LIMD1 ARNTAJUBA SUCCAUBB(77-152) TCEB2 AJUBA RPS27A(1-76) UBC(609-684) 2xHP-HIF1A UBC(609-684) PSMB7 EGLN1 UBB(77-152) EP300 PSMA3 UBC(1-76) 2OGPSMD8 2OGO2UBB(153-228) CUL2 RBX1 UBE2D3 UBC(381-456) 2xHP-HIF1A AJUBA EGLN3 UBC(77-152) HIF1A UBC(305-380) UBC(457-532) UBC(381-456) TCEB1 2xHP-EPAS1 PSMD5 UBE2D1,2,3:UbiquitinEGLN1 2xHP-HIF1A ELOC ELOB UBB(1-76) UBC(1-76) RPS27A(1-76) AJUBA HIF3A UBC(457-532) PSMC4 DNA2xHP-EPAS1 UBC(609-684) WTIP ARNT PSMD7 WTIP HIF3A HIF-alphaUBB(1-76) UBC(77-152) PSME2 ELOC UBC(229-304) 26S proteasomeUBC(381-456) UBC(153-228) HIF3AUBC(1-76) UBC(77-152) UBB(153-228) RPS27A(1-76) EGLN3 RPS27A(1-76) UBA52(1-76) UBC(609-684) RPS27A(1-76) RPS27A(1-76) UBB(1-76) HIF1A hydroxyPro-HIF-alpha:VHL:EloB,C:CUL2:RBX1:LIMD1,AJUBA,WTIP:PHD2,3UBB(153-228) UBC(533-608) 2xHP-EPAS1 PSMC2 UBC(229-304) UBB(1-76) UBC(153-228) UBB(153-228) RBX1 hydroxyPro-HIF-alpha:VHL:EloB,C:CUL2:RBX1PSMD13 UBB(153-228) EGLN2 VHL UBC(153-228) UBC(609-684) EPAS1 ELOB EPAS1 PSME4 PSMA5 CUL2 PSMD9 UBE2D3 2611, 20, 45, 68171731711229, 58296, 27, 36, 51, 62...172822


Description

In the presence of oxygen members of the transcription factor family HIF-alpha, comprising HIF1A, HIF2A (EPAS1), and HIF3A, are hydroxylated on proline residues by PHD1 (EGLN2), PHD2 (EGLN1), and PHD3 (EGLN3) and on asparagine residues by HIF1AN (FIH) (reviewed in Pouyssegur et al. 2006, Semenza 2007, Kaelin and Ratcliffe 2008, Nizet and Johnson 2009, Brahimi-Horn and Pouyssegur 2009, Majmundar et al. 2010, Loenarz and Schofield 2011). Both types of reaction require molecular oxygen as a substrate and it is probable that at least some HIF-alpha molecules carry both hydroxylated asparagine and hydroxylated proline (Tian et al. 2011).
Hydroxylated asparagine interferes with the ability of HIF-alpha to interact with p300 and CBP while hydroxylated proline facilitates the interaction of HIF-alpha with the E3 ubiquitin ligase VHL, causing ubiquitination and proteolysis of HIF-alpha. Hypoxia inhibits both types of hydroxylation, resulting in the stabilization of HIF-alpha, which then enters the nucleus, binds HIF-beta, and recruits p300 and CBP to activate target genes such as EPO and VEGF. View original pathway at:Reactome.

Comments

Reactome-Converter 
Pathway is converted from Reactome ID: 1234174
Reactome-version 
Reactome version: 66
Reactome Author 
Reactome Author: May, Bruce

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Bibliography

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History

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CompareRevisionActionTimeUserComment
101544view11:41, 1 November 2018ReactomeTeamreactome version 66
101079view21:23, 31 October 2018ReactomeTeamreactome version 65
100609view19:58, 31 October 2018ReactomeTeamreactome version 64
100160view16:42, 31 October 2018ReactomeTeamreactome version 63
99710view15:11, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99290view12:46, 31 October 2018ReactomeTeamreactome version 62
93972view13:48, 16 August 2017ReactomeTeamreactome version 61
93573view11:27, 9 August 2017ReactomeTeamreactome version 61
88138view12:54, 26 July 2016RyanmillerOntology Term : 'hypoxia inducible factor pathway' added !
88137view12:54, 26 July 2016RyanmillerOntology Term : 'regulatory pathway' added !
86674view09:23, 11 July 2016ReactomeTeamreactome version 56
83312view10:45, 18 November 2015ReactomeTeamVersion54
81762view10:08, 26 August 2015ReactomeTeamVersion53
76947view08:22, 17 July 2014ReactomeTeamFixed remaining interactions
76652view12:02, 16 July 2014ReactomeTeamFixed remaining interactions
76134view13:14, 11 June 2014AnweshaUpdated version
75039view13:55, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74683view08:45, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
26S proteasomeComplexR-HSA-68819 (Reactome)
2OGMetaboliteCHEBI:30915 (ChEBI)
2xHP-EPAS1 ProteinQ99814 (Uniprot-TrEMBL)
2xHP-EPAS1ProteinQ99814 (Uniprot-TrEMBL)
2xHP-HIF1A ProteinQ16665 (Uniprot-TrEMBL)
2xHP-HIF1AProteinQ16665 (Uniprot-TrEMBL)
AJUBA ProteinQ96IF1 (Uniprot-TrEMBL)
ARNT ProteinP27540 (Uniprot-TrEMBL)
ARNTProteinP27540 (Uniprot-TrEMBL)
CA9 geneGeneProductENSG00000107159 (Ensembl)
CA9ProteinQ16790 (Uniprot-TrEMBL)
CITED2ProteinQ99967 (Uniprot-TrEMBL)
CO2MetaboliteCHEBI:16526 (ChEBI)
CREBBP ProteinQ92793 (Uniprot-TrEMBL)
CREBBPProteinQ92793 (Uniprot-TrEMBL)
CUL2 ProteinQ13617 (Uniprot-TrEMBL)
DNA R-ALL-29428 (Reactome)
DNAR-ALL-29428 (Reactome)
EGLN1 ProteinQ9GZT9 (Uniprot-TrEMBL)
EGLN2 ProteinQ96KS0 (Uniprot-TrEMBL)
EGLN3 ProteinQ9H6Z9 (Uniprot-TrEMBL)
ELOB ProteinQ15370 (Uniprot-TrEMBL)
ELOC ProteinQ15369 (Uniprot-TrEMBL)
EP300 ProteinQ09472 (Uniprot-TrEMBL)
EP300ProteinQ09472 (Uniprot-TrEMBL)
EPAS1 ProteinQ99814 (Uniprot-TrEMBL)
EPAS1ProteinQ99814 (Uniprot-TrEMBL)
EPO geneGeneProductENSG00000130427 (Ensembl)
EPOProteinP01588 (Uniprot-TrEMBL)
FIH1:FIH1ComplexR-HSA-1235007 (Reactome)
HIF-alphaComplexR-HSA-1234147 (Reactome)
HIF-alphaComplexR-HSA-1234153 (Reactome)
HIF1A ProteinQ16665 (Uniprot-TrEMBL)
HIF1A,HIF2AComplexR-HSA-1234109 (Reactome)
HIF1AN ProteinQ9NWT6 (Uniprot-TrEMBL)
HIF1AProteinQ16665 (Uniprot-TrEMBL)
HIF3A ProteinQ9Y2N7 (Uniprot-TrEMBL)
HIF3AProteinQ9Y2N7 (Uniprot-TrEMBL)
HIF:CBP:p300ComplexR-HSA-1234099 (Reactome)
HIFComplexR-HSA-1234130 (Reactome)
HIGD1A geneGeneProductENSG00000181061 (Ensembl)
HIGD1AProteinQ9Y241 (Uniprot-TrEMBL)
HN-EPAS1 ProteinQ99814 (Uniprot-TrEMBL)
HN-HIF1A ProteinQ16665 (Uniprot-TrEMBL)
HP-HIF3A ProteinQ9Y2N7 (Uniprot-TrEMBL)
HP-HIF3AProteinQ9Y2N7 (Uniprot-TrEMBL)
LIMD1 ProteinQ9UGP4 (Uniprot-TrEMBL)
O2MetaboliteCHEBI:15379 (ChEBI)
PHD1,3ComplexR-HSA-1234124 (Reactome)
PHD2,3:LIMD1,AJUBA,WTIP:VHL:EloB:EloC:CUL2:RBX1ComplexR-HSA-8932458 (Reactome)
PSMA1 ProteinP25786 (Uniprot-TrEMBL)
PSMA2 ProteinP25787 (Uniprot-TrEMBL)
PSMA3 ProteinP25788 (Uniprot-TrEMBL)
PSMA4 ProteinP25789 (Uniprot-TrEMBL)
PSMA5 ProteinP28066 (Uniprot-TrEMBL)
PSMA6 ProteinP60900 (Uniprot-TrEMBL)
PSMA7 ProteinO14818 (Uniprot-TrEMBL)
PSMA8 ProteinQ8TAA3 (Uniprot-TrEMBL)
PSMB1 ProteinP20618 (Uniprot-TrEMBL)
PSMB10 ProteinP40306 (Uniprot-TrEMBL)
PSMB11 ProteinA5LHX3 (Uniprot-TrEMBL)
PSMB2 ProteinP49721 (Uniprot-TrEMBL)
PSMB3 ProteinP49720 (Uniprot-TrEMBL)
PSMB4 ProteinP28070 (Uniprot-TrEMBL)
PSMB5 ProteinP28074 (Uniprot-TrEMBL)
PSMB6 ProteinP28072 (Uniprot-TrEMBL)
PSMB7 ProteinQ99436 (Uniprot-TrEMBL)
PSMB8 ProteinP28062 (Uniprot-TrEMBL)
PSMB9 ProteinP28065 (Uniprot-TrEMBL)
PSMC1 ProteinP62191 (Uniprot-TrEMBL)
PSMC2 ProteinP35998 (Uniprot-TrEMBL)
PSMC3 ProteinP17980 (Uniprot-TrEMBL)
PSMC4 ProteinP43686 (Uniprot-TrEMBL)
PSMC5 ProteinP62195 (Uniprot-TrEMBL)
PSMC6 ProteinP62333 (Uniprot-TrEMBL)
PSMD1 ProteinQ99460 (Uniprot-TrEMBL)
PSMD10 ProteinO75832 (Uniprot-TrEMBL)
PSMD11 ProteinO00231 (Uniprot-TrEMBL)
PSMD12 ProteinO00232 (Uniprot-TrEMBL)
PSMD13 ProteinQ9UNM6 (Uniprot-TrEMBL)
PSMD14 ProteinO00487 (Uniprot-TrEMBL)
PSMD2 ProteinQ13200 (Uniprot-TrEMBL)
PSMD3 ProteinO43242 (Uniprot-TrEMBL)
PSMD4 ProteinP55036 (Uniprot-TrEMBL)
PSMD5 ProteinQ16401 (Uniprot-TrEMBL)
PSMD6 ProteinQ15008 (Uniprot-TrEMBL)
PSMD7 ProteinP51665 (Uniprot-TrEMBL)
PSMD8 ProteinP48556 (Uniprot-TrEMBL)
PSMD9 ProteinO00233 (Uniprot-TrEMBL)
PSME1 ProteinQ06323 (Uniprot-TrEMBL)
PSME2 ProteinQ9UL46 (Uniprot-TrEMBL)
PSME3 ProteinP61289 (Uniprot-TrEMBL)
PSME4 ProteinQ14997 (Uniprot-TrEMBL)
PSMF1 ProteinQ92530 (Uniprot-TrEMBL)
RBX1 ProteinP62877 (Uniprot-TrEMBL)
RPS27A(1-76) ProteinP62979 (Uniprot-TrEMBL)
SHFM1 ProteinP60896 (Uniprot-TrEMBL)
SUCCAMetaboliteCHEBI:15741 (ChEBI)
TCEB1 ProteinQ15369 (Uniprot-TrEMBL)
TCEB2 ProteinQ15370 (Uniprot-TrEMBL)
UBA52(1-76) ProteinP62987 (Uniprot-TrEMBL)
UBB(1-76) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(153-228) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(77-152) ProteinP0CG47 (Uniprot-TrEMBL)
UBC(1-76) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(153-228) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(229-304) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(305-380) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(381-456) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(457-532) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(533-608) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(609-684) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(77-152) ProteinP0CG48 (Uniprot-TrEMBL)
UBE2D1 ProteinP51668 (Uniprot-TrEMBL)
UBE2D1,2,3:UbiquitinComplexR-HSA-1234116 (Reactome)
UBE2D1,2,3:UbiquitinComplexR-HSA-1234123 (Reactome)
UBE2D1,2,3ComplexR-HSA-1234118 (Reactome)
UBE2D1,2,3ComplexR-HSA-1234120 (Reactome)
UBE2D2 ProteinP62837 (Uniprot-TrEMBL)
UBE2D3 ProteinP61077 (Uniprot-TrEMBL)
UbComplexR-HSA-113595 (Reactome)
VBC complex (with or without LIMD1)ComplexR-HSA-8932481 (Reactome)
VEGFA geneGeneProductENSG00000112715 (Ensembl)
VEGFAProteinP15692 (Uniprot-TrEMBL)
VHL ProteinP40337 (Uniprot-TrEMBL)
VHL:EloB,C:CUL2:RBX1ComplexR-HSA-1234141 (Reactome)
WTIP ProteinA6NIX2 (Uniprot-TrEMBL)
hydroxyAsn-HIF1A,HIF2AComplexR-HSA-1234148 (Reactome)
hydroxyPro-HIF-alpha:VHL:EloB,C:CUL2:RBX1:LIMD1,AJUBA,WTIP:PHD2,3ComplexR-HSA-1234125 (Reactome)
hydroxyPro-HIF-alpha:VHL:EloB,C:CUL2:RBX1ComplexR-HSA-1234101 (Reactome)
hydroxyPro-HIF-alphaComplexR-HSA-1234106 (Reactome)
hydroxyPro-HIF-alphaComplexR-HSA-1234132 (Reactome)
ub-HIF-alpha:VHL:EloB,C:CUL2:RBX1ComplexR-HSA-1234103 (Reactome)
ub-hydroxyPro-HIF-alpha:VCB (with or without LIMD1)ComplexR-HSA-8932465 (Reactome)
ub-hydroxyPro-HIF-alpha:VHL:EloB:EloC:CUL2:RBX1:LIMD1,AJUBA,WTIF:PHD2,3ComplexR-HSA-8932472 (Reactome)
ub-hydroxyPro-HIF-alpha:VHL:EloB:EloC:CUL2:RBX1ComplexR-HSA-1234138 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
26S proteasomemim-catalysisR-HSA-1234159 (Reactome)
2OGR-HSA-1234164 (Reactome)
2OGR-HSA-1234165 (Reactome)
2OGR-HSA-1234166 (Reactome)
2OGR-HSA-1234173 (Reactome)
2OGR-HSA-1234177 (Reactome)
2OGR-HSA-1234179 (Reactome)
2OGR-HSA-1234181 (Reactome)
2xHP-EPAS1ArrowR-HSA-1234166 (Reactome)
2xHP-EPAS1ArrowR-HSA-1234179 (Reactome)
2xHP-HIF1AArrowR-HSA-1234177 (Reactome)
2xHP-HIF1AArrowR-HSA-1234181 (Reactome)
ARNTR-HSA-1234171 (Reactome)
CA9 geneR-HSA-1235035 (Reactome)
CA9ArrowR-HSA-1235035 (Reactome)
CITED2TBarR-HSA-1234167 (Reactome)
CO2ArrowR-HSA-1234164 (Reactome)
CO2ArrowR-HSA-1234165 (Reactome)
CO2ArrowR-HSA-1234166 (Reactome)
CO2ArrowR-HSA-1234173 (Reactome)
CO2ArrowR-HSA-1234177 (Reactome)
CO2ArrowR-HSA-1234179 (Reactome)
CO2ArrowR-HSA-1234181 (Reactome)
CREBBPR-HSA-1234167 (Reactome)
DNAR-HSA-1234167 (Reactome)
EP300R-HSA-1234167 (Reactome)
EPAS1R-HSA-1234166 (Reactome)
EPAS1R-HSA-1234179 (Reactome)
EPO geneR-HSA-1235070 (Reactome)
EPOArrowR-HSA-1235070 (Reactome)
FIH1:FIH1mim-catalysisR-HSA-1234164 (Reactome)
HIF-alphaArrowR-HSA-1234161 (Reactome)
HIF-alphaR-HSA-1234161 (Reactome)
HIF-alphaR-HSA-1234171 (Reactome)
HIF1A,HIF2AR-HSA-1234164 (Reactome)
HIF1AR-HSA-1234177 (Reactome)
HIF1AR-HSA-1234181 (Reactome)
HIF3AR-HSA-1234165 (Reactome)
HIF3AR-HSA-1234173 (Reactome)
HIF:CBP:p300ArrowR-HSA-1234167 (Reactome)
HIF:CBP:p300ArrowR-HSA-1235035 (Reactome)
HIF:CBP:p300ArrowR-HSA-1235037 (Reactome)
HIF:CBP:p300ArrowR-HSA-1235070 (Reactome)
HIFArrowR-HSA-1234171 (Reactome)
HIFArrowR-HSA-8932184 (Reactome)
HIFR-HSA-1234167 (Reactome)
HIGD1A geneR-HSA-8932184 (Reactome)
HIGD1AArrowR-HSA-8932184 (Reactome)
HP-HIF3AArrowR-HSA-1234165 (Reactome)
HP-HIF3AArrowR-HSA-1234173 (Reactome)
O2R-HSA-1234164 (Reactome)
O2R-HSA-1234165 (Reactome)
O2R-HSA-1234166 (Reactome)
O2R-HSA-1234173 (Reactome)
O2R-HSA-1234177 (Reactome)
O2R-HSA-1234179 (Reactome)
O2R-HSA-1234181 (Reactome)
PHD1,3mim-catalysisR-HSA-1234165 (Reactome)
PHD1,3mim-catalysisR-HSA-1234166 (Reactome)
PHD1,3mim-catalysisR-HSA-1234181 (Reactome)
PHD2,3:LIMD1,AJUBA,WTIP:VHL:EloB:EloC:CUL2:RBX1R-HSA-1234183 (Reactome)
PHD2,3:LIMD1,AJUBA,WTIP:VHL:EloB:EloC:CUL2:RBX1mim-catalysisR-HSA-1234173 (Reactome)
PHD2,3:LIMD1,AJUBA,WTIP:VHL:EloB:EloC:CUL2:RBX1mim-catalysisR-HSA-1234177 (Reactome)
PHD2,3:LIMD1,AJUBA,WTIP:VHL:EloB:EloC:CUL2:RBX1mim-catalysisR-HSA-1234179 (Reactome)
R-HSA-1234159 (Reactome) Destruction of ubiquitinated HIF-alpha can occur in both the cytosol and nucleus (Berra et al. 2001). Upon reoxygenation of hypoxic cells HIF-alpha is ubiquitinated in the nucleus and transported to the cytosol in a complex with VHL:ElonginB:ElonginC:CUL2:RBX1 where it is destroyed (Groulx and Lee 2002, Jaakkola et al. 2001, Ivan et al. 2001)
R-HSA-1234161 (Reactome) HIF-alpha is translocated into the nucleus (Kallio et al. 1998, Depping et al. 2008, Chachami et al. 2009). Importin 4 and importin 7 (Chachami et al. 2009) as well as the importin alpha/beta pathway (Depping et al. 2008) appear to be capable of interacting with HIF-alpha. During hypoxia HIF-alpha accumulates in the nucleus where it associates with CBP and p300 (Kallio et al. 1998).
R-HSA-1234163 (Reactome) VHL is an E3 ubiquitin ligase that conjugates ubiquitin to hydroxylated HIF-alpha (Iwai et al. 1999, Kamura et al. 2000, Ohh et al. 2000, Groulx and Lee 2002, Maynard et al. 2003). VHL is predominantly cytosolic and shuttles between the cytosol and the nucleus (Lee et al. 1999, Groulx and Lee 2002). Ubiquitination and degradation of HIF-alpha can occur in both the cytosol and the nucleus (Berra et al. 2001).
R-HSA-1234164 (Reactome) HIF1AN (FIH, FIH-1) catalyzes the hydroxylation of an asparagine residue on each of HIF1A and HIF2A (Hewitson et al. 2002, Lando et al. 2002, Metzen et al. 2003, Lancaster et al. 2004). The reaction requires molecular oxygen as a substrate and is therefore inhibited by hypoxia.
R-HSA-1234165 (Reactome) Proline hydroxylases PHD1 (EGLN2) and PHD3 (EGLN3) located in the nucleus (Metzen et al. 2003) hydroxylate HIF3A at proline-492 (Hirsila et al. 2003, Maynard et al. 2003). Note that proline-492 of the reference isoform is proline-490 in isoform 2, the protein cited by Maynard et al. 2003. The amount of hydroxylation occurring in the nucleus is controversial. Most hydroxylation is believed to occur in the cytosol.
R-HSA-1234166 (Reactome) Proline hydroxylases PHD1 (EGLN2) and PHD3 (EGLN3) located in the nucleus hydroxylate HIF2A (EPAS1) at proline-405 and proline-531 (Hirsila et al. 2003, Percy et al. 2008, Furlow et al. 2009). The amount of hydroxylation occurring in the nucleus is controversial. Most hydroxylation is believed to be cytosolic.
R-HSA-1234167 (Reactome) HIF (heterodimer of HIF-alpha and HIF-beta) recruits p300 and CBP to the promoters of target genes (Kallio et al. 1998, Ebert and Bunn 1998, Ema et al. 1999, Gu et al. 2001, Dames et al. 2002, Freedman et al. 2002).
R-HSA-1234169 (Reactome) The VHL component of the VHL:ElonginB:ElonginC:CUL2:RBX1 binds HIF-alpha that have hydroxylated proline residues (Cockman et al. 2000, Ohh et al. 2000, Tanimoto et al. 2000, Jaakkola et al. 2001, Ivan et al. 2001, Yu et al. 2001, Bonicalzi et al. 2001). The VHL:HIF-alpha complex is predominantly nuclear (Lewis and Roberts 2003) however binding and degradation of HIF-alpha can also occur in the cytosol (Berra et al. 2001).
R-HSA-1234171 (Reactome) HIF-alpha (HIF1A, HIF2A (EPAS1), HIF3A) forms a heterodimer with ARNT (HIF1-beta) (Wang et al. 1995, Jiang et al. 1996, Tian et al. 1997, Gu et al. 1998, Erbel et al. 2003).
R-HSA-1234172 (Reactome) VHL is an E3 ubiquitin ligase that conjugates ubiquitin to hydroxylated HIF-alpha (Iwai et al. 1999, Kamura et al. 2000, Ohh et al. 2000, Groulx and Lee 2002, Maynard et al. 2003). VHL is predominantly cytosolic and shuttles between the cytosol and the nucleus (Lee et al. 1999, Groulx and Lee 2002). Ubiquitination and degradation of HIF-alpha can occur in both the cytosol and the nucleus (Berra et al. 2001). Upon return to normoxia from hypoxia most ubiquitinated HIF-alpha is nuclear (Groulx and Lee 2002).
R-HSA-1234173 (Reactome) Proline hydroxylases PHD2 (EGLN1) and PHD3 (EGLN3) located in the cytosol (Metzen et al. 2003) hydroxylate HIF3A at proline-492 (Hirsila et al. 2003, Maynard et al. 2003). A portion of PHD3 (EGLN3) is also located in the nucleus (Rantanen et al. 2008).
R-HSA-1234175 (Reactome) When hypoxic cells return to normoxia, HIF-alpha is ubiquitinated in the nucleus and exported to the cytosol (Groulx and Lee 2002). The shuttling of VHL between the nucleus and cytosol is required (Groulx and Lee 2002, Lee et al. 1999). Different cell types have different nucleocytoplasmic compartmentalization of HIF degradation (Zheng et al. 2006).
R-HSA-1234177 (Reactome) Proline hydroxylases PHD2 (EGLN1) and PHD3 (EGLN3) located in the cytosol (Metzen et al. 2003) hydroxylate HIF1A at proline-402 and proline-564 (Bruick and McKnight 2001, Jaakkola et al. 2001, Ivan et al. 2001, Ivan et al. 2002, Berra et al. 2003, Hirsila et al. 2003, Appelhoff et al. 2004, Tuckerman et al. 2004, Fedulova et al. 2007, Tian et al. 2011). A portion of PHD3 (EGLN3) is also located in the nucleus (Rantanen et al. 2008).
R-HSA-1234179 (Reactome) Proline hydroxylases PHD2 (EGLN1) and PHD3 (EGLN3) located in the cytosol (Metzen et al. 2003) hydroxylate EPAS1 (HIF2A) at proline-405 and proline-531 (Hirsila et al. 2003, Percy et al. 2008, Furlow et al. 2009). A portion of PHD3 (EGLN3) is also located in the nucleus (Rantanen et al. 2008).
R-HSA-1234181 (Reactome) Proline hydroxylases PHD1 (EGLN2) and PHD3 (EGLN3) located in the nucleus (Metzen et al. 2003) hydroxylate HIF1A at proline-402 and proline-564 (Buick and McKnight 2001, Jaakkola et al. 2001, Ivan et al. 2001, Ivan et al. 2002, Berra et al. 2003, Hirsila et al. 2003, Appelhoff et al. 2004, Tuckerman et al. 2004, Fedulova et al. 2007, Tian et al. 2011). The amount of hydroxylation occurring in the nucleus is controversial. Most hydroxylation is believed to occur in the cytosol.
R-HSA-1234183 (Reactome) VHL within the VHL:ElonginB:ElonginC:CUL2:RBX1 Complex binds HIF-alpha subunits that have hydroxylated proline residues (Cockman et al. 2000, Ohh et al. 2000, Tanimoto et al. 2000, Jaakkola et al. 2001, Ivan et al. 2001, Yu et al. 2001). VHL constitutively shuttles between the cytosol and nucleoplasm (Lewis and Roberts 2003) and though the VHL:HIF-alpha complex is predominantly nuclear, binding and degradation can occur in both the cytosol and the nucleus (Berra et al. 2001).
R-HSA-1235035 (Reactome) The gene encoding carbonic anhydrase IX (CA9) is transcribed to yield mRNA and the mRNA is translated to yield protein. Hypoxia-inducible factor binds the promoter of CA9 and enhances expression of CA9.
R-HSA-1235037 (Reactome) The VEGFA (VEGF) gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Hypoxia-inducible factor binds the VEGF promoter, recruits p300 and CBP, and enhances transcription.
R-HSA-1235070 (Reactome) The EPO gene is transcribed to yield mRNA and the mRNA is translated to yield protein. Transcription of EPO is enhanced by Hypoxia-inducible factor, which binds to the EPO promoter.
R-HSA-8932184 (Reactome) The HIGD1A (RCF1A, HIG1) gene is transcribed to yield mRNA and the mRNA is translated to yield protein (Ameri et al. 2015). Expression of HIGD1A is transactivated by HIF in response to hypoxia (Ameri et al. 2015).
SUCCAArrowR-HSA-1234164 (Reactome)
SUCCAArrowR-HSA-1234165 (Reactome)
SUCCAArrowR-HSA-1234166 (Reactome)
SUCCAArrowR-HSA-1234173 (Reactome)
SUCCAArrowR-HSA-1234177 (Reactome)
SUCCAArrowR-HSA-1234179 (Reactome)
SUCCAArrowR-HSA-1234181 (Reactome)
UBE2D1,2,3:UbiquitinR-HSA-1234163 (Reactome)
UBE2D1,2,3:UbiquitinR-HSA-1234172 (Reactome)
UBE2D1,2,3ArrowR-HSA-1234163 (Reactome)
UBE2D1,2,3ArrowR-HSA-1234172 (Reactome)
UbArrowR-HSA-1234159 (Reactome)
VBC complex (with or without LIMD1)ArrowR-HSA-1234159 (Reactome)
VEGFA geneR-HSA-1235037 (Reactome)
VEGFAArrowR-HSA-1235037 (Reactome)
VHL:EloB,C:CUL2:RBX1R-HSA-1234169 (Reactome)
hydroxyAsn-HIF1A,HIF2AArrowR-HSA-1234164 (Reactome)
hydroxyPro-HIF-alpha:VHL:EloB,C:CUL2:RBX1:LIMD1,AJUBA,WTIP:PHD2,3ArrowR-HSA-1234183 (Reactome)
hydroxyPro-HIF-alpha:VHL:EloB,C:CUL2:RBX1:LIMD1,AJUBA,WTIP:PHD2,3R-HSA-1234163 (Reactome)
hydroxyPro-HIF-alpha:VHL:EloB,C:CUL2:RBX1:LIMD1,AJUBA,WTIP:PHD2,3mim-catalysisR-HSA-1234163 (Reactome)
hydroxyPro-HIF-alpha:VHL:EloB,C:CUL2:RBX1ArrowR-HSA-1234169 (Reactome)
hydroxyPro-HIF-alpha:VHL:EloB,C:CUL2:RBX1R-HSA-1234172 (Reactome)
hydroxyPro-HIF-alpha:VHL:EloB,C:CUL2:RBX1mim-catalysisR-HSA-1234172 (Reactome)
hydroxyPro-HIF-alphaR-HSA-1234169 (Reactome)
hydroxyPro-HIF-alphaR-HSA-1234183 (Reactome)
ub-HIF-alpha:VHL:EloB,C:CUL2:RBX1ArrowR-HSA-1234172 (Reactome)
ub-HIF-alpha:VHL:EloB,C:CUL2:RBX1R-HSA-1234175 (Reactome)
ub-hydroxyPro-HIF-alpha:VCB (with or without LIMD1)R-HSA-1234159 (Reactome)
ub-hydroxyPro-HIF-alpha:VHL:EloB:EloC:CUL2:RBX1:LIMD1,AJUBA,WTIF:PHD2,3ArrowR-HSA-1234163 (Reactome)
ub-hydroxyPro-HIF-alpha:VHL:EloB:EloC:CUL2:RBX1ArrowR-HSA-1234175 (Reactome)
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