Reactome | Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha

Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha

Stable Identifier

R-HSA-1234176

Type

Pathway

Species

Homo sapiens

Compartment

cytosol, nucleoplasm

ReviewStatus

5/5

Locations in the PathwayBrowser

Expand all

General

SBML | | PDF

SVG | | PPTX | SBGN

Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha

Click the image above or here to open this pathway in the Pathway Browser

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).
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.

Literature References

PubMed ID	Title	Journal	Year
11598268	A conserved family of prolyl-4-hydroxylases that modify HIF McKnight, SL, Bruick, RK	Science	2001
21335549	Differential sensitivity of HIF hydroxylation sites to hypoxia and hydroxylase inhibitors Willam, C, Lee, MK, Yeoh, KK, Tian, YM, Edelmann, MJ, Kessler, BM, Kramer, HB, Schofield, CJ, Pugh, CW, Ratcliffe, PJ, Eriksson, T	J Biol Chem	2011
12912907	HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia Benizri, E, Pouysségur, J, Ginouvès, A, Volmat, V, Roux, D, Berra, E	EMBO J	2003
12615973	Intracellular localisation of human HIF-1 alpha hydroxylases: implications for oxygen sensing Stengel, P, Klinger, M, Acker, H, Hellwig-Bürgel, T, Fandrey, J, Wotzlaw, C, Metzen, E, Berchner-Pfannschmidt, U, Huang, WQ, Marxsen, JH, Stolze, I, Jelkmann, W	J Cell Sci	2003
18184961	A gain-of-function mutation in the HIF2A gene in familial erythrocytosis McMullin, MF, Furlow, PW, Li, X, Lucas, GS, Percy, MJ, Lappin, TR	N Engl J Med	2008
11292862	HIFalpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing Lane, WS, Asara, JM, Kim, W, Salic, A, Valiando, J, Ivan, M, Kaelin WG, Jr, Ohh, M, Kondo, K, Yang, H	Science	2001
19208626	Erythrocytosis-associated HIF-2alpha mutations demonstrate a critical role for residues C-terminal to the hydroxylacceptor proline McMullin, MF, Furlow, PW, Percy, MJ, Lappin, TR, Bierl, C, Master, SR, Sutherland, S	J Biol Chem	2009
15247232	Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor Gleadle, JM, Tian, YM, Raval, RR, Harris, AL, Turley, H, Pugh, CW, Ratcliffe, PJ, Appelhoff, RJ	J Biol Chem	2004
12351678	Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor Günzler, V, Sorokina, I, Gervasi, DC, Haberberger, T, Ivan, M, Kaelin WG, Jr, Kondo, K, Conaway, JW, Yang, H, Michelson, KS, Conaway, RC	Proc Natl Acad Sci U S A	2002
12788921	Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor Hirsilä, M, Günzler, V, Koivunen, P, Myllyharju, J, Kivirikko, KI	J Biol Chem	2003
15474027	Determination and comparison of specific activity of the HIF-prolyl hydroxylases Tuckerman, JR, Mole, DR, Hewitson, KS, Tian, YM, Zhao, Y, Pugh, CW, Ratcliffe, PJ	FEBS Lett	2004
11292861	Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation Gielbert, J, Gaskell, SJ, Maxwell, PH, Mukherji, M, Pugh, CW, Mole, DR, Kriegsheim, Av, Jaakkola, P, Tian, YM, Wilson, MI, Hebestreit, HF, Schofield, CJ, Ratcliffe, PJ	Science	2001
12538644	Multiple splice variants of the human HIF-3 alpha locus are targets of the von Hippel-Lindau E3 ubiquitin ligase complex Lee, EH, Chung, J, Maynard, MA, Qi, H, Ohh, M, Conaway, JW, Kondo, Y, Hara, S, Conaway, RC	J Biol Chem	2003
17434750	Expression and purification of catalytically active human PHD3 in Escherichia coli Bergquist, J, Fedulova, N, Hanrieder, J, Emrén, LO	Protein Expr Purif	2007