Cytosolic Hydroxylation of Proline Residues on EPAS1 (HIF2A) Nuclear Hydroxylation of Proline Residues on EPAS1 (HIF2A) Nuclear Hydroxylation of Proline Residues on HIF1A Cytosolic Hydroxylation of Proline Residues on HIF1A Cytosolic Hydroxylation of Proline Residues on HIF3A Nuclear VHL:EloB/C:CUL2:RBX1 Complex Binds HIF-alpha Hydroxylated at Proline Residues Nuclear Hydroxylation of Proline Residues on HIF3A Cytosolic VHL:EloB/C:CUL2:RBX1 Complex Binds HIF-alpha Hydroxylated at Proline Residues Destruction of Ubiquitinated HIF-alpha by the Proteasome Nuclear Ubiquitination of HIF-alpha Nuclear Export of Ubiquitinated HIF-alpha:VHL:EloB/C:CUL2:RBX1 Complex Cytosolic Ubiquitination of HIF-alpha PathwayStep7260 PathwayStep7261 PathwayStep7250 PathwayStep7252 PathwayStep7251 PathwayStep7254 PathwayStep7253 PathwayStep7256 PathwayStep7255 PathwayStep7258 PathwayStep7257 PathwayStep7259 Oxygen-dependent Proline Hydroxylation of Hypoxia-inducible Factor Alpha Authored: May, B, 2011-03-09 Edited: May, B, 2011-03-09 HIF-alpha subunits, comprising HIF1A (Bruick and McKnight 2001, Ivan et al. 2001, Jaakkola et al. 2001), HIF2A (Percy et al. 2008, Furlow et al. 2009), and HIF3A (Maynard et al. 2003), are hydroxylated at proline residues by the prolyl hydroxylases PHD1 (EGLN2), PHD2 (EGLN1), and PHD3 (EGLN3) (Bruick and McKnight 2001, Berra et al. 2003, Hirsila et al. 2003, Metzen et al. 2003, Tuckerman et al. 2004, Appelhoff et al. 2004, Fedulova et al. 2007, Tian et al. 2011). The reaction requires molecular oxygen as a substrate and so it is inhibited by hypoxia. PHD2 (EGLN1) is predominantly cytosolic (Metzen et al. 2003) and is the key determinant in the regulation of HIF-alpha subunits by oxygen (Berra et al. 2003).<br>HIF-alpha subunits hydroxylated at proline residues are bound by VHL, an E3 ubiquitin ligase in a complex containing ElonginB, Elongin C, CUL2, and RBX1. VHL ubiquitinates HIF-alpha, resulting in destruction of HIF-alpha by proteolysis. Hypoxia inhibits proline hydroxylation and interaction with VHL, stabilizing HIF-alpha, which transits to the nucleus and activates gene expression. Pubmed11292861 Pubmed11292862 Pubmed11598268 Pubmed12351678 Pubmed12538644 Pubmed12615973 Pubmed12788921 Pubmed12912907 Pubmed15247232 Pubmed15474027 Pubmed17434750 Pubmed18184961 Pubmed19208626 Pubmed21335549 Reactome Database ID Release 431234176 Reactome, http://www.reactome.org ReactomeREACT_120916 Reviewed: Rantanen, Krista, 2012-05-19