PHD1–3 (prolyl hydroxylases 1–3) catalyse the hydroxylation of HIF (hypoxia-inducible factor)-α subunit that triggers the substrate ubiquitination and subsequent degradation. The RING (really interesting new gene) finger E3 ligase Siah2 preferentially targets PHD3 for degradation. Here, we identify the requirements for such selective targeting. Firstly, PHD3 lacks an N-terminal extension found in PHD1 and PHD2; deletion of this domain from PHD1 and PHD2 renders them susceptible to degradation by Siah2. Secondly, PHD3 can homo- and hetero-multimerize with other PHDs. Consequently, PHD3 is found in high-molecular-mass fractions that were enriched in hypoxia. Interestingly, within the lower-molecular-mass complex, PHD3 exhibits higher specific activity towards hydroxylation of HIF-1α and co-localizes with Siah2, suggesting that Siah2 limits the availability of the more active form of PHD3. These findings provide new insight into the mechanism underlying the regulation of PHD3 availability and activity in hypoxia by the E3 ligase Siah2.
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Research Article|
December 11 2006
Hypoxia-induced assembly of prolyl hydroxylase PHD3 into complexes: implications for its activity and susceptibility for degradation by the E3 ligase Siah2
Koh Nakayama;
Koh Nakayama
*Signal Transduction Program, Burnham Institute for Medical Research, La Jolla, CA 92037, U.S.A.
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Stefan Gazdoiu;
Stefan Gazdoiu
†Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY 10029, U.S.A.
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Robert Abraham;
Robert Abraham
‡Oncology Research, Wyeth Pharmaceuticals, Pearl River, NY 10965, U.S.A.
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Zhen-Qiang Pan;
Zhen-Qiang Pan
†Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY 10029, U.S.A.
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Ze'ev Ronai
Ze'ev Ronai
1
*Signal Transduction Program, Burnham Institute for Medical Research, La Jolla, CA 92037, U.S.A.
1To whom correspondence should be addressed (email ronai@burnham.org).
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Publisher: Portland Press Ltd
Received:
July 26 2006
Revision Received:
August 24 2006
Accepted:
September 08 2006
Accepted Manuscript online:
September 08 2006
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2007
Biochem J (2007) 401 (1): 217–226.
Article history
Received:
July 26 2006
Revision Received:
August 24 2006
Accepted:
September 08 2006
Accepted Manuscript online:
September 08 2006
Citation
Koh Nakayama, Stefan Gazdoiu, Robert Abraham, Zhen-Qiang Pan, Ze'ev Ronai; Hypoxia-induced assembly of prolyl hydroxylase PHD3 into complexes: implications for its activity and susceptibility for degradation by the E3 ligase Siah2. Biochem J 1 January 2007; 401 (1): 217–226. doi: https://doi.org/10.1042/BJ20061135
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