Cellular response to hypoxia (Homo sapiens)

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9-11, 14, 25...4, 9, 15, 19, 21...3, 2813, 372, 32, 40, 4513, 20, 34, 37, 38, 53...21, 22, 40, 41, 606, 46, 48, 52, 556, 8, 18, 26, 5121, 40, 41, 6016, 27, 3013, 20, 34, 37, 38, 53...4, 13, 38, 5820-22, 404, 12, 13, 17, 31...20, 21, 404, 9, 15, 19, 21...4, 12, 17, 31, 34...5, 7, 265, 23, 24, 29, 30, 33...Ub hydroxyPro-HIF-alpha UBE2D1,2,3Ubiquitin HIF-alpha ubiquitin nucleoplasmUBE2D1,2,3Ubiquitin hydroxyPro-HIF-alphaVHLEloB/CCUL2RBX1 ub-HIF-alphaVHLEloB/CCUL2RBX1 UBE2D1/2/3 VBC complex UBE2D1,2,3 hydroxyPro-HIF-alpha ub-HIF-alpha cytosolhydroxyPro-HIF-alphaVHLEloB/CCUL2RBX1 RBX1-CUL2-EloB/C-VHL RBX1-CUL2-EloB/C-VHL ubiquitin RBX1-CUL2-EloB/C-VHL HIFCBPp300 VHLEloB/CCUL2RBX1 ub-hydroxyPro-HIF-alphaVHLEloB/CCUL2RBX1 HIF FIH1FIH1 HIF VHLEloB/CCUL2RBX1 VHLEloB/CCUL2RBX1 Ub VBC Complex ub-hydroxyPro-HIF-alpha VBC Complex hydroxyPro-HIF-alpha hydroxyPro-HIF-alpha VBC complex HIF-alpha VBC complex VBC Complex CUL2 PHD2/3UBCUBBVHL HIF3AhydroxyPro-HIF-alphaVHLEloB/CCUL2RBX1UBE2D1,2,3UbiquitinTCEB2 2xHP-EPAS1 CUL2 HIF1A 2xHP-HIF1A ub-hydroxyPro-HIF-alphaVHLEloB/CCUL2RBX1UBE2D3 RPS27AUBA52RPS27AUBCUBBSUCCAhydroxyPro-HIF-alphaCUL2 UBCTCEB1 UBBUBE2D1 RBX1 UBE2D3 EPAS12xHP-HIF1A UBCTCEB2 UBA52VHL HIF3AUBCUBChydroxyPro-HIF-alphaVHLEloB/CCUL2RBX1UBCUBCUBE2D1/2/3UBCUBCUBE2D1,2,32xHP-HIF1A2OGUBBVHL UBCUBCUBCHIF1A HIF1A2OGCO2UBB2xHP-HIF1A CO2UBE2D2 UBBUBB2xHP-EPAS1 VHL UBE2D2 EPAS1UBChydroxyAsn-HIF1A/HIF2AUBC2xHP-HIF1A UBCHP-HIF3A ub-HIF-alphaVHLEloB/CCUL2RBX1TCEB1 EP3002xHP-HIF1ATCEB1 CREBBPUBCEPOO2SUCCAUBC2xHP-EPAS1 HIF3A CREBBPUBCHIF-alphaUBCO2CUL2 UBCRBX1 VHLEloB/CCUL2RBX1UBCHP-HIF3A2xHP-EPAS1RBX1 CO2UBCTCEB2 UBBRPS27ARPS27A2xHP-EPAS1UBCUBBSUCCATCEB2 UBE2D1,2,3UbiquitinFIH1FIH12OGO2UBCCA9VEGFAUBCTCEB1 HP-HIF3A HIF1ANRBX1-CUL2-EloB/C-VHLHP-HIF3A UBCCO2HIF1A/HIF2AHIFRBX1 SUCCAUBE2D1 SUCCAHP-HIF3A UBCPHD1/3VHL EPAS1 UBA52TCEB1 EP300UBC2OGHIFCBPp300HIF1AHIF-alphaUBCEPAS1 2OGUBCUBBUBCARNTHIF3A CO2UBBDNARBX1 CUL2 UBCO2TCEB2 RBX1 UBCHP-HIF3AARNTARNTUbhydroxyPro-HIF-alpha2xHP-EPAS1 O2VHL UBCUBCCUL2 TCEB2 TCEB1 UBBUBA524045123, 24, 29, 30, 33...4013, 37, 39


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. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=1234174

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Bibliography

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History

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CompareRevisionActionTimeUserComment
114982view16:51, 25 January 2021ReactomeTeamReactome version 75
113426view11:50, 2 November 2020ReactomeTeamReactome version 74
112628view16:01, 9 October 2020ReactomeTeamReactome version 73
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
2OGMetaboliteCHEBI:30915 (ChEBI)
2xHP-EPAS1 ProteinQ99814 (Uniprot-TrEMBL)
2xHP-EPAS1ProteinQ99814 (Uniprot-TrEMBL)
2xHP-HIF1A ProteinQ16665 (Uniprot-TrEMBL)
2xHP-HIF1AProteinQ16665 (Uniprot-TrEMBL)
ARNTProteinP27540 (Uniprot-TrEMBL)
CA9ProteinQ16790 (Uniprot-TrEMBL)
CO2MetaboliteCHEBI:16526 (ChEBI)
CREBBPProteinQ92793 (Uniprot-TrEMBL)
CUL2 ProteinQ13617 (Uniprot-TrEMBL)
DNAREACT_3913 (Reactome)
EP300ProteinQ09472 (Uniprot-TrEMBL)
EPAS1 ProteinQ99814 (Uniprot-TrEMBL)
EPAS1ProteinQ99814 (Uniprot-TrEMBL)
EPOProteinP01588 (Uniprot-TrEMBL)
FIH1 FIH1ComplexREACT_124556 (Reactome)
HIF

CBP

p300		ComplexREACT_125616 (Reactome)
HIF-alphaProteinREACT_124671 (Reactome)
HIF-alphaProteinREACT_125189 (Reactome)
HIF1A ProteinQ16665 (Uniprot-TrEMBL)
HIF1A/HIF2AProteinREACT_125211 (Reactome)
HIF1ANProteinQ9NWT6 (Uniprot-TrEMBL)
HIF1AProteinQ16665 (Uniprot-TrEMBL)
HIF3A ProteinQ9Y2N7 (Uniprot-TrEMBL)
HIF3AProteinQ9Y2N7 (Uniprot-TrEMBL)
HIFComplexREACT_121564 (Reactome)
HP-HIF3A ProteinQ9Y2N7 (Uniprot-TrEMBL)
HP-HIF3AProteinQ9Y2N7 (Uniprot-TrEMBL)
O2MetaboliteCHEBI:15379 (ChEBI)
PHD1/3ProteinREACT_125306 (Reactome)
PHD2/3ProteinREACT_125291 (Reactome)
RBX1 ProteinP62877 (Uniprot-TrEMBL)
RBX1-CUL2-EloB/C-VHLComplexREACT_76823 (Reactome)
RPS27AProteinP62979 (Uniprot-TrEMBL)
SUCCAMetaboliteCHEBI:15741 (ChEBI)
TCEB1 ProteinQ15369 (Uniprot-TrEMBL)
TCEB2 ProteinQ15370 (Uniprot-TrEMBL)
UBA52ProteinP62987 (Uniprot-TrEMBL)
UBBProteinP0CG47 (Uniprot-TrEMBL)
UBCProteinP0CG48 (Uniprot-TrEMBL)
UBE2D1 ProteinP51668 (Uniprot-TrEMBL)
UBE2D1,2,3 UbiquitinComplexREACT_124982 (Reactome)
UBE2D1,2,3 UbiquitinComplexREACT_124997 (Reactome)
UBE2D1,2,3ProteinREACT_122290 (Reactome)
UBE2D1/2/3ProteinREACT_125348 (Reactome)
UBE2D2 ProteinP62837 (Uniprot-TrEMBL)
UBE2D3 ProteinP61077 (Uniprot-TrEMBL)
UbProteinREACT_3316 (Reactome)
VEGFAProteinP15692 (Uniprot-TrEMBL)
VHL

EloB/C CUL2

RBX1		ComplexREACT_124578 (Reactome)
VHL ProteinP40337 (Uniprot-TrEMBL)
hydroxyAsn-HIF1A/HIF2AProteinREACT_124608 (Reactome)
hydroxyPro-HIF-alpha

VHL EloB/C CUL2

RBX1		ComplexREACT_121940 (Reactome)
hydroxyPro-HIF-alpha

VHL EloB/C CUL2

RBX1		ComplexREACT_124934 (Reactome)
hydroxyPro-HIF-alphaProteinREACT_124785 (Reactome)
hydroxyPro-HIF-alphaProteinREACT_124968 (Reactome)
ub-HIF-alpha

VHL EloB/C CUL2

RBX1		ComplexREACT_122640 (Reactome)
ub-hydroxyPro-HIF-alpha

VHL EloB/C CUL2

RBX1		ComplexREACT_124595 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
2OGREACT_120822 (Reactome)
2OGREACT_120825 (Reactome)
2OGREACT_120885 (Reactome)
2OGREACT_120945 (Reactome)
2OGREACT_120973 (Reactome)
2OGREACT_121198 (Reactome)
2OGREACT_121242 (Reactome)
2xHP-EPAS1ArrowREACT_120822 (Reactome)
2xHP-EPAS1ArrowREACT_120885 (Reactome)
2xHP-HIF1AArrowREACT_120825 (Reactome)
2xHP-HIF1AArrowREACT_120973 (Reactome)
ARNTREACT_121202 (Reactome)
CO2ArrowREACT_120822 (Reactome)
CO2ArrowREACT_120825 (Reactome)
CO2ArrowREACT_120885 (Reactome)
CO2ArrowREACT_120945 (Reactome)
CO2ArrowREACT_120973 (Reactome)
CO2ArrowREACT_121198 (Reactome)
CO2ArrowREACT_121242 (Reactome)
CREBBPREACT_121196 (Reactome)
DNAREACT_121196 (Reactome)
EP300REACT_121196 (Reactome)
EPAS1REACT_120822 (Reactome)
EPAS1REACT_120885 (Reactome)
FIH1 FIH1mim-catalysisREACT_121198 (Reactome)
HIF

CBP

p300		ArrowREACT_121133 (Reactome)
HIF

CBP

p300		ArrowREACT_121365 (Reactome)
HIF

CBP

p300		ArrowREACT_121407 (Reactome)
HIF-alphaREACT_121202 (Reactome)
HIF1A/HIF2AREACT_121198 (Reactome)
HIF1AREACT_120825 (Reactome)
HIF1AREACT_120973 (Reactome)
HIF3AREACT_120945 (Reactome)
HIF3AREACT_121242 (Reactome)
HIFREACT_121196 (Reactome)
HP-HIF3AArrowREACT_120945 (Reactome)
HP-HIF3AArrowREACT_121242 (Reactome)
O2REACT_120822 (Reactome)
O2REACT_120825 (Reactome)
O2REACT_120885 (Reactome)
O2REACT_120945 (Reactome)
O2REACT_120973 (Reactome)
O2REACT_121198 (Reactome)
O2REACT_121242 (Reactome)
PHD1/3mim-catalysisREACT_120885 (Reactome)
PHD1/3mim-catalysisREACT_120945 (Reactome)
PHD1/3mim-catalysisREACT_120973 (Reactome)
PHD2/3mim-catalysisREACT_120822 (Reactome)
PHD2/3mim-catalysisREACT_120825 (Reactome)
PHD2/3mim-catalysisREACT_121242 (Reactome)
RBX1-CUL2-EloB/C-VHLArrowREACT_120788 (Reactome)
RBX1-CUL2-EloB/C-VHLREACT_120795 (Reactome)
REACT_120788 (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)
REACT_120795 (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).
REACT_120822 (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).
REACT_120825 (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).
REACT_120857 (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).
REACT_120876 (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).
REACT_120885 (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.
REACT_120945 (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.
REACT_120954 (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).
REACT_120973 (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.
REACT_121002 (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).
REACT_121133 (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.
REACT_121196 (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).
REACT_121198 (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.
REACT_121202 (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).
REACT_121242 (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).
REACT_121365 (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.
REACT_121374 (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).
REACT_121407 (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.
SUCCAArrowREACT_120822 (Reactome)
SUCCAArrowREACT_120825 (Reactome)
SUCCAArrowREACT_120885 (Reactome)
SUCCAArrowREACT_120945 (Reactome)
SUCCAArrowREACT_120973 (Reactome)
SUCCAArrowREACT_121198 (Reactome)
SUCCAArrowREACT_121242 (Reactome)
UBE2D1,2,3 UbiquitinREACT_120954 (Reactome)
UBE2D1,2,3 UbiquitinREACT_121374 (Reactome)
UBE2D1,2,3ArrowREACT_121374 (Reactome)
UBE2D1/2/3ArrowREACT_120954 (Reactome)
UbArrowREACT_120788 (Reactome)
VHL

EloB/C CUL2

RBX1		REACT_120876 (Reactome)
hydroxyAsn-HIF1A/HIF2AArrowREACT_121198 (Reactome)
hydroxyPro-HIF-alpha

VHL EloB/C CUL2

RBX1		REACT_120954 (Reactome)
hydroxyPro-HIF-alpha

VHL EloB/C CUL2

RBX1		REACT_121374 (Reactome)
hydroxyPro-HIF-alpha

VHL EloB/C CUL2

RBX1		mim-catalysisREACT_120954 (Reactome)
hydroxyPro-HIF-alpha

VHL EloB/C CUL2

RBX1		mim-catalysisREACT_121374 (Reactome)
hydroxyPro-HIF-alphaREACT_120795 (Reactome)
hydroxyPro-HIF-alphaREACT_120876 (Reactome)
ub-HIF-alpha

VHL EloB/C CUL2

RBX1		ArrowREACT_121374 (Reactome)
ub-hydroxyPro-HIF-alpha

VHL EloB/C CUL2

RBX1		ArrowREACT_120954 (Reactome)
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