EGLN1 / PHD2

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 HIF1B. 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. EGLN1 is the most important isozyme under normoxia and, through regulating the stability of HIF1, involved in various hypoxia-influenced processes such as angiogenesis in retinal and cardiac functionality. Target proteins are preferencially recognized via a LXXLAP motif.

Publications (42)

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]

OS-9 interacts with hypoxia-inducible factor 1alpha and prolyl hydroxylases to promote oxygen-dependent degradation of HIF-1alpha. Baek JH, Mahon PC, Oh J, Kelly B, Krishnamachary B, Pearson M, Chan DA, Giaccia AJ, Semenza GL. Molecular cell. 2005 17:503-12. (IP; Human) [PubMed:15721254]

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]

Concordant regulation of gene expression by hypoxia and 2-oxoglutarate-dependent dioxygenase inhibition: the role of HIF-1alpha, HIF-2alpha, and other pathways. Elvidge GP, Glenny L, Appelhoff RJ, Ratcliffe PJ, Ragoussis J, Gleadle JM. The Journal of biological chemistry. 2006 281:15215-26. (WB; Human) [PubMed:16565084]

Dynamic HIF1A regulation during human placental development. Ietta F, Wu Y, Winter J, Xu J, Wang J, Post M, Caniggia I. Biology of reproduction. 2006 75:112-21. (WB; Human) [PubMed:16611863]

Immunodetection of human telomerase reverse-transcriptase (hTERT) re-appraised: nucleolin and telomerase cross paths. Wu YL, Dudognon C, Nguyen E, Hillion J, Pendino F, Tarkanyi I, Aradi J, Lanotte M, Tong JH, Chen GQ, Sgal-Bendirdjian E. Journal of cell science. 2006 119:2797-806. [PubMed:16772337]

Transforming growth factor beta1 induces hypoxia-inducible factor-1 stabilization through selective inhibition of PHD2 expression. McMahon S, Charbonneau M, Grandmont S, Richard DE, Dubois CM. The Journal of biological chemistry. 2006 281:24171-81. (WB; Human) [PubMed:16815840]

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]

Mucin 1 oncoprotein blocks hypoxia-inducible factor 1alpha activation in a survival response to hypoxia. Yin L, Kharbanda S, Kufe D. The Journal of biological chemistry. 2007 282:257-66. (WB; Human) [PubMed:17102128]

The peptidyl prolyl cis/trans isomerase FKBP38 determines hypoxia-inducible transcription factor prolyl-4-hydroxylase PHD2 protein stability. Barth S, Nesper J, Hasgall PA, Wirthner R, Nytko KJ, Edlich F, Katschinski DM, Stiehl DP, Wenger RH, Camenisch G. Molecular and cellular biology. 2007 27:3758-68. (WB; Human) [PubMed:17353276] [PMC:PMC1899990]

The new tumor-suppressor gene inhibitor of growth family member 4 (ING4) regulates the production of proangiogenic molecules by myeloma cells and suppresses hypoxia-inducible factor-1 alpha (HIF-1alpha) activity: involvement in myeloma-induced angiogenesi. Colla S, Tagliaferri S, Morandi F, Lunghi P, Donofrio G, Martorana D, Mancini C, Lazzaretti M, Mazzera L, Ravanetti L, Bonomini S, Ferrari L, Miranda C, Ladetto M, Neri TM, Neri A, Greco A, Mangoni M, Bonati A, Rizzoli V, Giuliani N. Blood. 2007 110:4464-75. [PubMed:17848618]

The von Hippel-Lindau tumor suppressor protein and Egl-9-Type proline hydroxylases regulate the large subunit of RNA polymerase II in response to oxidative stress. Mikhaylova O, Ignacak ML, Barankiewicz TJ, Harbaugh SV, Yi Y, Maxwell PH, Schneider M, Van Geyte K, Carmeliet P, Revelo MP, Wyder M, Greis KD, Meller J, Czyzyk-Krzeska MF. Molecular and cellular biology. 2008 28:2701-17. [PubMed:18285459] [PMC:PMC2293119]

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]

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]

Melanoma antigen-11 inhibits the hypoxia-inducible factor prolyl hydroxylase 2 and activates hypoxic response. Aprelikova O, Pandolfi S, Tackett S, Ferreira M, Salnikow K, Ward Y, Risinger JI, Barrett JC, Niederhuber J. Cancer research. 2009 69:616-24. (ICC, WB, IP; Human) [PubMed:19147576] [PMC:PMC2629394]

Prolyl hydroxylase 2 deficiency limits proliferation of vascular smooth muscle cells by hypoxia-inducible factor-1{alpha}-dependent mechanisms. Schultz K, Murthy V, Tatro JB, Beasley D. American journal of physiology. Lung cellular and molecular physiology. 2009 296:L921-7. (WB; Human) [PubMed:19304911] [PMC:PMC2692800]

HIF-prolyl hydroxylases in the rat kidney: physiologic expression patterns and regulation in acute kidney injury. Schdel J, Klanke B, Weidemann A, Buchholz B, Bernhardt W, Bertog M, Amann K, Korbmacher C, Wiesener M, Warnecke C, Kurtz A, Eckardt KU, Willam C. The American journal of pathology. 2009 174:1663-74. (WB; Mouse) [PubMed:19349364] [PMC:PMC2671255]

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]

Longitudinal and multimodal in vivo imaging of tumor hypoxia and its downstream molecular events. Lehmann S, Stiehl DP, Honer M, Dominietto M, Keist R, Kotevic I, Wollenick K, Ametamey S, Wenger RH, Rudin M. Proceedings of the National Academy of Sciences of the United States of America. 2009 106:14004-9. [PubMed:19666490] [PMC:PMC2729010]

Mint3 enhances the activity of hypoxia-inducible factor-1 (HIF-1) in macrophages by suppressing the activity of factor inhibiting HIF-1. Sakamoto T, Seiki M. The Journal of biological chemistry. 2009 284:30350-9. [PubMed:19726677] [PMC:PMC2781590]

Expression of delta-like ligand 4 (Dll4) and markers of hypoxia in colon cancer. Jubb AM, Turley H, Moeller HC, Steers G, Han C, Li JL, Leek R, Tan EY, Singh B, Mortensen NJ, Noguera-Troise I, Pezzella F, Gatter KC, Thurston G, Fox SB, Harris AL. British journal of cancer. 2009 101:1749-57. [PubMed:19844231] [PMC:PMC2778546]

Retention of prolyl hydroxylase PHD2 in the cytoplasm prevents PHD2-induced anchorage-independent carcinoma cell growth. Jokilehto T, Hgel H, Heikkinen P, Rantanen K, Elenius K, Sundstrm J, Jaakkola PM. Experimental cell research. 2010 316:1169-78. (IHC, WB; Human) [PubMed:20156434]

Prolyl hydroxylase domain (PHD) 2 affects cell migration and F-actin formation via RhoA/rho-associated kinase-dependent cofilin phosphorylation. Vogel S, Wottawa M, Farhat K, Zieseniss A, Schnelle M, Le-Huu S, von Ahlen M, Malz C, Camenisch G, Katschinski DM. The Journal of biological chemistry. 2010 285:33756-63. (WB; Human) [PubMed:20801873] [PMC:PMC2962474]

Hypoxia-inducible factor-1 contributes to the profibrotic action of angiotensin II in renal medullary interstitial cells. Wang Z, Tang L, Zhu Q, Yi F, Zhang F, Li PL, Li N. Kidney international. 2011 79:300-10. [PubMed:20881940] [PMC:PMC3107572]

Cardiomyocyte-specific prolyl-4-hydroxylase domain 2 knock out protects from acute myocardial ischemic injury. Hlscher M, Silter M, Krull S, von Ahlen M, Hesse A, Schwartz P, Wielockx B, Breier G, Katschinski DM, Zieseniss A. The Journal of biological chemistry. 2011 286:11185-94. [PubMed:21270129] [PMC:PMC3064173]

Induction of hypoxia inducible factor (HIF-1) in rat kidneys by iron chelation with the hydroxypyridinone, CP94. Baek JH, Reiter CE, Manalo DJ, Buehler PW, Hider RC, Alayash AI. Biochimica et biophysica acta. 1809:262-8. (WB, IP; Human) [PubMed:21558026]

The function of hypoxia-inducible factor (HIF) is independent of the endoplasmic reticulum protein OS-9. Brockmeier U, Platzek C, Schneider K, Patak P, Bernardini A, Fandrey J, Metzen E. PloS one. 2011 6:e19151. (WB; Human) [PubMed:21559462] [PMC:PMC3084761]

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]

Impaired hypoxic response in senescent mouse brain. Rabie T, Kunze R, Marti HH. International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience. 2011 29:655-61. [PubMed:21704147]

Expressions of individual PHDs associate with good prognostic factors and increased proliferation in breast cancer patients. Peurala E, Koivunen P, Bloigu R, Haapasaari KM, Jukkola-Vuorinen A. Breast cancer research and treatment. 2012 133:179-88. (IHC; Human) [PubMed:21877141]

Activation of the HIF prolyl hydroxylase by the iron chaperones PCBP1 and PCBP2. Nandal A, Ruiz JC, Subramanian P, Ghimire-Rijal S, Sinnamon RA, Stemmler TL, Bruick RK, Philpott CC. Cell metabolism. 2011 14:647-57. (WB; Human) [PubMed:22055506] [PMC:PMC3361910]

Synthetic transactivation screening reveals ETV4 as broad coactivator of hypoxia-inducible factor signaling. Wollenick K, Hu J, Kristiansen G, Schraml P, Rehrauer H, Berchner-Pfannschmidt U, Fandrey J, Wenger RH, Stiehl DP. Nucleic acids research. 2012 40:1928-43. [PubMed:22075993] [PMC:PMC3300025]

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]

Overexpression of factor inhibiting HIF-1 enhances vessel maturation and tumor growth via platelet-derived growth factor-C. Kuzmanov A, Wielockx B, Rezaei M, Kettelhake A, Breier G. International journal of cancer. Journal international du cancer. 2012 131:E603-13. [PubMed:22095574]

Inactivation of prolyl hydroxylase domain (PHD) protein by epigallocatechin (EGCG) stabilizes hypoxia-inducible factor (HIF-1) and induces hepcidin (Hamp) in rat kidney. Manalo DJ, Baek JH, Buehler PW, Struble E, Abraham B, Alayash AI. Biochemical and biophysical research communications. 2011 416:421-6. [PubMed:22138393]

Role of reactive oxygen species in the regulation of HIF-1 by prolyl hydroxylase 2 under mild hypoxia. Niecknig H, Tug S, Reyes BD, Kirsch M, Fandrey J, Berchner-Pfannschmidt U. Free radical research. 2012 46:705-17. (WB; Human) [PubMed:22360728]

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]

Investigation of possible endogenous hypoxia markers in colorectal cancer. Verstraete M, Debucquoy A, Devos E, Sagaert X, Penninckx F, Begg A, Haustermans K. International journal of radiation biology. 2013 89:15-Sep. (IHC; Human) [PubMed:22852555]

Lactate activates HIF-1 in oxidative but not in Warburg-phenotype human tumor cells. De Saedeleer CJ, Copetti T, Porporato PE, Verrax J, Feron O, Sonveaux P. PloS one. 2012 7:e46571. (WB; Human) [PubMed:23082126] [PMC:PMC3474765]

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Gene Name:	egl-9 family hypoxia-inducible factor 1
Synonyms:	EGLN1, C1orf12, EGL9, ECYT3, Egl nine-like protein 1, HIFPH2, HIF prolyl hydroxylase 2, HIF-PH2, HIF-prolyl hydroxylase 2, ZMYND6, PHD2, SM20, EGL nine (C.elegans) homolog 1, Egl nine homolog 1, HPH-2, HPH2, SM-20
Target Sequences:	NM_022051 NP_071334.1 Q9GZT9

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EGLN1 / PHD2

egl-9 family hypoxia-inducible factor 1

Publications (42)

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