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EGLN3 / PHD3

egl-9 family hypoxia-inducible factor 3

Cellular oxygen sensor that catalyzes, under normoxic conditions, the post-translational formation of 4-hydroxyproline in hypoxia-inducible factor (HIF) alpha proteins. Hydroxylates a specific proline found in each of the oxygen-dependent degradation (ODD) domains (N-terminal, NODD, and C-terminal, CODD) of HIF1A. Also hydroxylates HIF2A. Has a preference for the CODD site for both HIF1A and HIF2A. Hydroxylation on the NODD site by EGLN3 appears to require prior hydroxylation on the CODD site. Hydroxylated HIFs are then targeted for proteasomal degradation via the von Hippel-Lindau ubiquitination complex. Under hypoxic conditions, the hydroxylation reaction is attenuated allowing HIFs to escape degradation resulting in their translocation to the nucleus, heterodimerization with HIF1B, and increased expression of hypoxy-inducible genes. EGLN3 is the most important isozyme in limiting physiological activation of HIFs (particularly HIF2A) in hypoxia. Also hydroxylates PKM in hypoxia, limiting glycolysis. Under normoxia, hydroxylates and regulates the stability of ADRB2. Regulator of cardiomyocyte and neuronal apoptosis. In cardiomyocytes, inhibits the anti-apoptotic effect of BCL2 by disrupting the BAX-BCL2 complex. In neurons, has a NGF-induced proapoptotic effect, probably through regulating CASP3 activity. Also essential for hypoxic regulation of neutrophilic inflammation. Plays a crucial role in DNA damage response (DDR) by hydroxylating TELO2, promoting its interaction with ATR which is required for activation of the ATR/CHK1/p53 pathway. Target proteins are preferencially recognized via a LXXLAP motif.

Gene Name:	egl-9 family hypoxia-inducible factor 3
Synonyms:	EGLN3, HPH-1, HIF prolyl hydroxylase 3, HIF-prolyl hydroxylase 3, HIFPH3, PHD3, EGL nine (C.elegans) homolog 3, Egl nine homolog 3, HIF-PH3, HIFP4H3
Target Sequences:	NM_022073 NP_071356.1 Q9H6Z9

Publications (19)

Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor. Appelhoff RJ, Tian YM, Raval RR, Turley H, Harris AL, Pugh CW, Ratcliffe PJ, Gleadle JM. The Journal of biological chemistry. 2004 279:38458-65. [PubMed:15247232]

Genetic analysis of the role of the asparaginyl hydroxylase factor inhibiting hypoxia-inducible factor (FIH) in regulating hypoxia-inducible factor (HIF) transcriptional target genes [corrected]. Stolze IP, Tian YM, Appelhoff RJ, Turley H, Wykoff CC, Gleadle JM, Ratcliffe PJ. The Journal of biological chemistry. 2004 279:42719-25. [PubMed:15302861]

Activation of hypoxia-inducible factors in hyperoxia through prolyl 4-hydroxylase blockade in cells and explants of primate lung. Asikainen TM, Schneider BK, Waleh NS, Clyman RI, Ho WB, Flippin LA, Gnzler V, White CW. Proceedings of the National Academy of Sciences of the United States of America. 2005 102:10212-7. (WB; Human) [PubMed:16009933] [PMC:PMC1177409]

Use of novel monoclonal antibodies to determine the expression and distribution of the hypoxia regulatory factors PHD-1, PHD-2, PHD-3 and FIH in normal and neoplastic human tissues. Soilleux EJ, Turley H, Tian YM, Pugh CW, Gatter KC, Harris AL. Histopathology. 2005 47:602-10. [PubMed:16324198]

Overexpression and nuclear translocation of hypoxia-inducible factor prolyl hydroxylase PHD2 in head and neck squamous cell carcinoma is associated with tumor aggressiveness. Jokilehto T, Rantanen K, Luukkaa M, Heikkinen P, Grenman R, Minn H, Kronqvist P, Jaakkola PM. Clinical cancer research : an official journal of the American Association for Cancer Research. 2006 12:1080-7. (IHC, WB; Human) [PubMed:16489060]

Enhancement of angiogenic effectors through hypoxia-inducible factor in preterm primate lung in vivo. Asikainen TM, Waleh NS, Schneider BK, Clyman RI, White CW. American journal of physiology. Lung cellular and molecular physiology. 2006 291:L588-95. [PubMed:16679381]

Expression and actions of HIF prolyl-4-hydroxylase in the rat kidneys. Li N, Yi F, Sundy CM, Chen L, Hilliker ML, Donley DK, Muldoon DB, Li PL. American journal of physiology. Renal physiology. 2007 292:F207-16. (WB, IHC-P; Rat) [PubMed:16885149]

EGLN3 prolyl hydroxylase regulates skeletal muscle differentiation and myogenin protein stability. Fu J, Menzies K, Freeman RS, Taubman MB. The Journal of biological chemistry. 2007 282:12410-8. [PubMed:17344222]

Prolyl hydroxylase PHD3 activates oxygen-dependent protein aggregation. Rantanen K, Pursiheimo J, Hgel H, Himanen V, Metzen E, Jaakkola PM. Molecular biology of the cell. 2008 19:2231-40. (ICC; Human) [PubMed:18337469] [PMC:PMC2366864]

PHDs overactivation during chronic hypoxia "desensitizes" HIFalpha and protects cells from necrosis. Ginouvs A, Ilc K, Macas N, Pouyssgur J, Berra E. Proceedings of the National Academy of Sciences of the United States of America. 2008 105:4745-50. [PubMed:18347341] [PMC:PMC2290777]

mAKAP compartmentalizes oxygen-dependent control of HIF-1alpha. Wong W, Goehring AS, Kapiloff MS, Langeberg LK, Scott JD. Science signaling. 2008 1:ra18. [PubMed:19109240] [PMC:PMC2828263]

Oxygen-regulated beta(2)-adrenergic receptor hydroxylation by EGLN3 and ubiquitylation by pVHL. Xie L, Xiao K, Whalen EJ, Forrester MT, Freeman RS, Fong G, Gygi SP, Lefkowitz RJ, Stamler JS. Science signaling. 2009 2:ra33. [PubMed:19584355] [PMC:PMC2788937]

Expression of the cellular oxygen sensor PHD2 (EGLN-1) predicts radiation sensitivity in squamous cell cancer of the head and neck. Luukkaa M, Jokilehto T, Kronqvist P, Vahlberg T, Grnman R, Jaakkola P, Minn H. International journal of radiation biology. 2009 85:900-8. [PubMed:19639506]

Aberrant promoter CpG methylation is a mechanism for impaired PHD3 expression in a diverse set of malignant cells. Place TL, Fitzgerald MP, Venkataraman S, Vorrink SU, Case AJ, Teoh ML, Domann FE. PloS one. 2011 6:e14617. (WB; Human) [PubMed:21297970] [PMC:PMC3030558]

Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Luo W, Hu H, Chang R, Zhong J, Knabel M, O'Meally R, Cole RN, Pandey A, Semenza GL. Cell. 2011 145:732-44. (WB, ChrIP; Human) [PubMed:21620138] [PMC:PMC3130564]

Regulation of cellular levels of Sprouty2 protein by prolyl hydroxylase domain and von Hippel-Lindau proteins. Anderson K, Nordquist KA, Gao X, Hicks KC, Zhai B, Gygi SP, Patel TB. The Journal of biological chemistry. 2011 286:42027-36. [PubMed:22006925] [PMC:PMC3234935]

Prolyl hydroxylase PHD3 enhances the hypoxic survival and G1 to S transition of carcinoma cells. Hgel H, Rantanen K, Jokilehto T, Grenman R, Jaakkola PM. PloS one. 2011 6:e27112. (WB; Human) [PubMed:22087251] [PMC:PMC3210766]

Expression of prolyl hydroxylases (PHDs) is selectively controlled by HIF-1 and HIF-2 proteins in nucleus pulposus cells of the intervertebral disc: distinct roles of PHD2 and PHD3 proteins in controlling HIF-1 activity in hypoxia. Fujita N, Markova D, Anderson DG, Chiba K, Toyama Y, Shapiro IM, Risbud MV. The Journal of biological chemistry. 2012 287:16975-86. (ICC, WB; Human, Rat) [PubMed:22451659] [PMC:PMC3351286]

Prolyl hydroxylase 3 (PHD3) modulates catabolic effects of tumor necrosis factor- (TNF-) on cells of the nucleus pulposus through co-activation of nuclear factor B (NF-B)/p65 signaling. Fujita N, Gogate SS, Chiba K, Toyama Y, Shapiro IM, Risbud MV. The Journal of biological chemistry. 2012 287:39942-53. (WB; Rat) [PubMed:22948157] [PMC:PMC3501017]

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The data on this page has been compiled from LifeSpan internal sources, the National Center for Biotechnology Information (NCBI), and The Universal Protein Resource (UniProt).

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