VHL:EloB,C:NEDD8-CUL2:RBX1 complex ubiquitinylates HIF-alpha

Stable Identifier
R-HSA-8956106
Type
Reaction
Species
Homo sapiens
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Summation

VHL is the substrate binding protein of a CUL2-based E3 ubiquitin ligase complex 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).

Literature References
PubMed ID Title Journal Year
11454738 Hypoxia-inducible factor-1 alpha (HIF-1 alpha) escapes O(2)-driven proteasomal degradation irrespective of its subcellular localization: nucleus or cytoplasm

Berra, E, Roux, D, Richard, DE, Pouysségur, J

EMBO Rep 2001
12538644 Multiple splice variants of the human HIF-3 alpha locus are targets of the von Hippel-Lindau E3 ubiquitin ligase complex

Maynard, MA, Qi, H, Chung, J, Lee, EH, Kondo, Y, Hara, S, Conaway, RC, Conaway, JW, Ohh, M

J Biol Chem 2003
10973499 Activation of HIF1alpha ubiquitination by a reconstituted von Hippel-Lindau (VHL) tumor suppressor complex

Kamura, T, Sato, S, Iwai, K, Czyzyk-Krzeska, M, Conaway, RC, Conaway, JW

Proc Natl Acad Sci U S A 2000
9891082 Transcription-dependent nuclear-cytoplasmic trafficking is required for the function of the von Hippel-Lindau tumor suppressor protein

Lee, S, Neumann, M, Stearman, R, Stauber, R, Pause, A, Pavlakis, GN, Klausner, RD

Mol Cell Biol 1999
10878807 Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein

Ohh, M, Park, CW, Ivan, M, Hoffman, MA, Kim, TY, Huang, LE, Pavletich, N, Chau, V, Kaelin, WG

Nat Cell Biol 2000
10535940 Identification of the von Hippel-lindau tumor-suppressor protein as part of an active E3 ubiquitin ligase complex

Iwai, K, Yamanaka, K, Kamura, T, Minato, N, Conaway, RC, Conaway, JW, Klausner, RD, Pause, A

Proc Natl Acad Sci U S A 1999
12101228 Oxygen-dependent ubiquitination and degradation of hypoxia-inducible factor requires nuclear-cytoplasmic trafficking of the von Hippel-Lindau tumor suppressor protein

Groulx, I, Lee, S

Mol Cell Biol 2002
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Title
ubiquitin-protein transferase activity of RBX1:NEDD8-CUL2:EloB,C:VHL:COMMDs:CCDC22:DCUN1D1,2,4,5:hydroxyPro-HIF-alpha [cytosol]
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