The DOI matches its Crossref record; 34 of the 34 references it cites were found in a registry or an index.
Asparaginyl Hydroxylation of the Notch Ankyrin Repeat Domain by Factor Inhibiting Hypoxia-inducible Factor
Open accessAbstract
The stability and activity of hypoxia-inducible factor (HIF) are regulated by the post-translational hydroxylation of specific prolyl and asparaginyl residues. We show that the HIF asparaginyl hydroxylase, factor inhibiting HIF (FIH), also catalyzes hydroxylation of highly conserved asparaginyl residues within ankyrin repeat (AR) domains (ARDs) of endogenous Notch receptors. AR hydroxylation decreases the extent of ARD binding to FIH while not affecting signaling through the canonical Notch pathway. ARD proteins were found to efficiently compete with HIF for FIH-dependent hydroxylation. Crystallographic analyses of the hydroxylated Notch ARD (2.35A) and of Notch peptides bound to FIH (2.4-2.6A) reveal the stereochemistry of hydroxylation on the AR and imply that significant conformational changes are required in the ARD fold in order to enable hydroxylation at the FIH active site. We propose that ARD proteins function as natural inhibitors of FIH and that the hydroxylation status of these proteins provides another oxygen-dependent interface that modulates HIF signaling.
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“It also seems that increased NF-κB activity in hypoxia can be regulated by HIF-144, thus a cross-regulatory loop may exist between these two pathways and may involve other transcriptional regulators that bear non-redundant PHD sensitivity, including activating transcription factor-4 and Notch52,53”
From Hypoxia: an alarm signal during intestinal inflammation (2010) · cites this paper as [52]
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“…Species Method Reference Skp1/Fbw7/CyclinE N-term degron 2ovr human X-ray (Hao et al., 2007) Factor Inhibiting HIF-1 (FIH)/Notch1 peptide N/A mouse X-ray (Coleman et al., 2007) FIH/Notch1 peptide N/A mouse X-ray (Coleman et al., 2007) J Cell Sci. Author manuscript; available in PMC 2009 June 15.”
InfluentialOxygen sensing and hypoxia signalling pathways in animals: The implications of physiology for cancer
Ratcliffe, P. J. (2013) · The Journal of Physiology · doi:10.1113/jphysiol.2013.251470 · Cited by 294
“These proteins show a high affinity for FIH and are abundant in cells, so that they might be predicted to compete with HIF for hydroxylation (Coleman et al. 2007; Wilkins et al. 2009).”
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“In contrast to EGLNs, FIH is relatively promiscuous, as it can hydroxylate a broad spectrum of additional substrates, including Notch (Coleman et al., 2007), cytoskeletal Ankyrin family proteins (Yang et al., 2011a), and the TRPV3 ion channel (Karttunen et al., 2015).”
Structural studies on human 2-oxoglutarate dependent oxygenases
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Self-citationZheng, X., Linke, S., Dias, J. M., Zheng, X., Gradin, K., Wallis, T. P., Hamilton, B. R., Gustafsson, M. V., Ruas, J. L., Wilkins, S. E., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0711591105 · Cited by 271
“During the preparation of this paper, a study describing similar data for the modification of Notch by FIH-1 was published (18).”
MethodNotch inhibitors for cancer treatment
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“1.1.2.5 Hydroxylation: It have been described that the asparagine hydroxylase factorinhibiting HIF1α (FIH1α), which also operates in the cellular hypoxic response, hydroxylates NIC at two residues (N1945 and N2012) (Coleman et al., 2007; Zheng et al., 2008).”
BackgroundInfluentialHypoxia, hypoxia-inducible factors (HIF), HIF hydroxylases and oxygen sensing
Webb, J. D., Coleman, M. L., & Pugh, C. W. (2009) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-009-0147-7 · Cited by 261
“It has been shown that ARDs competitively inhibit FIH-mediated HIF-alpha CAD hydroxylation [146].”
BackgroundSelf-citationThe Asparaginyl Hydroxylase Factor Inhibiting HIF-1α Is an Essential Regulator of Metabolism
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“The impaired ROS generation observed in Hif1a þ/2 HET mice is in striking contrast to the enhanced ROS production that has been demonstrated in Epas1 2/2 mice, 39,40 which lack expression of HIF-2a, a protein that dimerizes with HIF-1b and can regulate gene transcription either in concert with, or in opposition to, HI…”
BackgroundMolecular and cellular mechanisms of HIF prolyl hydroxylase inhibitors in clinical trials
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“Notch-2 Hydroxylation DANAQ N 1905 N 1904 [40,41,42] FIH ND”
InfluentialTankyrases: Structure, Function and Therapeutic Implications in Cancer
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“Hydroxylation could also modulate hypoxic response by regulating the amount of FIH that is bound to ankyrin repeat domains and thus its availability to hydroxylate Hypoxia-inducible factor 1-alpha (HIF1 ) [99, 101].”
BackgroundTian, Y., Yeoh, K. K., Lee, M. K., Eriksson, T., Kessler, B. M., Kramer, H., Edelmann, M. J., Willam, C., Pugh, C. W., Schofield, C. J., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.211110 · Cited by 191
Self-citationProtein Hydroxylation Catalyzed by 2-Oxoglutarate-dependent Oxygenases
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“It is proposed that competition between ARDs and HIF- for FIH can modulate the role of FIH in the hypoxic response (62).”
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“The released NICD is then translocated into the nucleus for transcriptional activation of Notch target genes such as Hes1, Hey1, and cyclin D1 [294-296].”
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“(32, 33), However, because FIH did not regulate nuclear factor-nB or Notch transcriptional response, the significance of FIH-mediated hydroxylation remains unclear in ARD proteins other than HIF-a.”
BackgroundBernhardt, W. M., Göttmann, U., Doyon, F., Buchholz, B., Câmpean, V., Schödel, J., Reisenbuechler, A., Klaus, S. J., Arend, M., Flippin, L. A., et al. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0903978106 · Cited by 150
“Coleman ML, et al. (2007) Asparaginyl hydroxylation of the Notch ankyrin repeat domain by factor inhibiting hypoxia-inducible factor.”
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BackgroundInfluentialYang, M. H., Ge, W., Chowdhury, R., Claridge, T. D. W., Kramer, H., Schmierer, B., McDonough, M. A., Gong, L., Kessler, B. M., Ratcliffe, P. J., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.193540 · Cited by 73
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Self-citationChan, M. C., Atasoylu, O., Hodson, E. J., Tumber, A., Leung, I. K. H., Chowdhury, R., Gómez‐Pérez, V., Demetriades, M., Rydzik, A. M., Holt‐Martyn, J. P., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0132004 · Cited by 71
“IOX2 and IOX4 are highly selective PHD inhibitors–this is important given the roles of other 2OG oxygenases; FIH has multiple substrates other than HIFα [45,46,47,48,49,50,51] and the JumonjiC histone demethylases (KDMs) are generally important in the regulation of gene expression [52].”
BackgroundSelf-citationModulating Notch signaling by pathway-intrinsic and pathway-extrinsic mechanisms
Poellinger, L., & Lendahl, U. (2008) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2008.07.013 · Cited by 67
Hypoxia: how does the monocyte-macrophage system respond to changes in oxygen availability?
Strehl, C., Fangradt, M., Fearon, U., Gaber, T., Buttgereit, F., & Veale, D. J. (2013) · Journal of Leukocyte Biology · doi:10.1189/jlb.1212627 · Cited by 68
Sakamoto, T., & Seiki, M. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.019216 · Cited by 62
Post-translational modifications of connexin26 revealed by mass spectrometry
Locke, D., Bian, S., Hong Li, A., & Harris, A. L. (2009) · Biochemical Journal · doi:10.1042/bj20091140 · Cited by 62
MicroRNA‐31 targets FIH‐1 to positively regulate corneal epithelial glycogen metabolism
Peng, H., Hamanaka, R. B., Katsnelson, J., Hao, L., Yang, W., Chandel, N. S., & Lavker, R. M. (2012) · The FASEB Journal · doi:10.1096/fj.11-198515 · Cited by 63
“In addition to HIF-1 , FIH-1 has been shown to hydroxylate ankyrin repeat domain (ARD)-containing proteins, such as Notch (21, 22).”
BackgroundNew Insights into Protein Hydroxylation and Its Important Role in Human Diseases
Zurlo, G., Guo, J., Takada, M., Wei, W., & Zhang, Q. H. (2016) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2016.09.004 · Cited by 62
Wilkins, S. E., Hyvärinen, J., Chicher, J., Gorman, J. J., Peet, D. J., Bilton, R. L., & Koivunen, P. (2009) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2009.01.005 · Cited by 61
Yustein, J. T., Liu, Y.-C., Gao, P., Jie, C., Le, A., Vuica‐Ross, M., Chng, W. J., Eberhart, C. G., Bergsagel, P. L., & Dang, C. V. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0901230107 · Cited by 58
“We speculate that increased N levels through Jagged2 expression could reciprocally inhibit factor-inhibiting HIF (FIH) and augment HIF function to provide a hypoxic growth advantage independent of Notch target genes (30).”
BackgroundAsparagine β-hydroxylation stabilizes the ankyrin repeat domain fold
Kelly, L., McDonough, M. A., Coleman, M. L., Ratcliffe, P. J., & Schofield, C. J. (2008) · Molecular BioSystems · doi:10.1039/b815271c · Cited by 61
Self-citationChen, T., Yao, L.-Q., Shi, Q., Ren, Z., Ye, L., Xu, J., Zhou, P., & Zhong, Y. (2014) · Cancer Biology & Therapy · doi:10.4161/cbt.28017 · Cited by 58
Identification of non-histone substrates for JMJD2A–C histone demethylases
Ponnaluri, V. K. C., Vavilala, D. T., Putty, S., Gutheil, W. G., & Mukherji, M. (2009) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2009.09.107 · Cited by 57
Lawton, M., Tong, M., Gündoğan, F., Wands, J. R., & de la Monte, S. M. (2010) · Oxidative Medicine and Cellular Longevity · doi:10.4161/oxim.3.5.13296 · Cited by 58
MicroRNAs in the cornea: Role and implications for treatment of corneal neovascularization
Mukwaya, A., Jensen, L. D., Peebo, B. B., & Lagali, N. (2019) · The Ocular Surface · doi:10.1016/j.jtos.2019.04.002 · Cited by 56
“In agreement with targeting FIH-1, miRNA-31 was shown to promote colorectal cancer by targeting FIH-1 in HCT116 and SW1116 cell lines 60 .”
InfluentialMantri, M., Loik, N. D., Hamed, R. B., Claridge, T. D. W., McCullagh, J., & Schofield, C. J. (2011) · ChemBioChem · doi:10.1002/cbic.201000641 · Cited by 55
Self-citationTandem-repeat proteins: regularity plus modularity equals design-ability
Javadi, Y., & Itzhaki, L. S. (2013) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2013.06.011 · Cited by 54
Janke, K., Brockmeier, U., Kuhlmann, K., Eisenacher, M., Nolde, J., Meyer, H. E., Mairbäurl, H., & Metzen, E. (2013) · Journal of Cell Science · doi:10.1242/jcs.117564 · Cited by 53
Ratcliffe, P. P., & Bishop, T. (2014) · Hypoxia · doi:10.2147/hp.s47598 · Cited by 55
“FIH-catalyzed hydroxylation of asparagine residues within the ankyrin consensus has been demonstrated both in vivo and in vitro and the target hydroxylation has been visualized by nuclear magnetic resonance (NMR) and X-ray methods as well as MS. 178,179 Interestingly, within the context of ARD proteins, FIH can cataly…”
Self-citationThe Inflammatory Tissue Microenvironment in IBD
Colgan, S. P., Curtis, V. F., & Campbell, E. L. (2013) · Inflammatory Bowel Diseases · doi:10.1097/mib.0b013e31828dcaaf · Cited by 52
Modulation of the Hypoxic Response
Pugh, C. W. (2016) · Advances in experimental medicine and biology · doi:10.1007/978-1-4899-7678-9_18 · Cited by 57
The how’s and why’s of protein folding intermediates
Tsytlonok, M., & Itzhaki, L. S. (2012) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2012.10.006 · Cited by 51
Introduction to Structural Studies on 2-Oxoglutarate-Dependent Oxygenases and Related Enzymes
Aik, W. S., Chowdhury, R., Clifton, I. J., Hopkinson, R. J., Leissing, T. M., McDonough, M. A., Nowak, R. P., Schofield, C. J., & Walport, L. J. (2015) · Royal Society of Chemistry eBooks · doi:10.1039/9781782621959-00059 · Cited by 52
Self-citationMartínez-Noël, G., Luck, K., Kühnle, S., Desbuleux, A., Szajner, P., Galligan, J. T., Rodriguez, D., Zheng, L., Boyland, K. A., Leclere, F., et al. (2018) · Journal of Molecular Biology · doi:10.1016/j.jmb.2018.01.021 · Cited by 53
Decoding the PTM-switchboard of Notch
Antfolk, D., Antila, C., Kemppainen, K., Landor, S. K.-J., & Sahlgren, C. (2019) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2019.07.002 · Cited by 52
Folding and Stability of Ankyrin Repeats Control Biological Protein Function
Kumar, A., & Balbach, J. (2021) · Biomolecules · doi:10.3390/biom11060840 · Cited by 51
“Nank undergoes hydroxylation at one or more asparagines at the side chain Cβ position [88,89].”
BackgroundKim, S., Lee, M., & Choi, Y. K. (2019) · Biomolecules & Therapeutics · doi:10.4062/biomolther.2019.119 · Cited by 48
“Moreover, FIH-1 hydroxylates ankyrin repeat domains in Notch receptors, thereby decreasing their activity and FIH ability to hydroxylate HIFs (Coleman et al., 2007).”
BackgroundNotch signaling, hypoxia, and cancer
Guo, M., Niu, Y., Xie, M., Liu, X., & Li, X. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2023.1078768 · Cited by 48
Bertagna, A. M., Toptygin, D. D., Brand, L., & Barrick, D. (2008) · Biochemical Society Transactions · doi:10.1042/bst0360157 · Cited by 50
Schmierer, B., Novák, B., & Schofield, C. J. (2010) · BMC Systems Biology · doi:10.1186/1752-0509-4-139 · Cited by 44
“More recently, it has become clear that HIFa is not the only FIH substrate, but that FIH also catalyses the hydroxylation of a wide range of other proteins [11-16].”
BackgroundResultInfluentialSelf-citationRawłuszko-Wieczorek, A. A., Bujnicka, K. E., Horbacka, K., Krokowicz, P., & Jagodziński, P. P. (2013) · BMC Cancer · doi:10.1186/1471-2407-13-526 · Cited by 44
“Additionally, FIH exerts HIF-independent functions by interaction with pVHL, histone deacetylases, p105, Notch 1, and SOCS box proteins [55-58].”
Metadata
- Authors
- Coleman, M. L., McDonough, M. A., Hewitson, K. S., Coles, C., Mecinovicí, J., Edelmann, M., Cook, K. M., Cockman, M. E., Lancaster, D. E., Kessler, B. M., Oldham, N. J., Ratcliffe, P. J., & Schofield, C. J.
- Affiliations
- University of Oxford (GB)
- Corresponding author
- Schofield, Christopher J.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2007-08
- Volume
- 282
- Issue
- 33
- Pages
- 24027-24038
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2078263362
- Cited by
- 222
- References
- 34
- Citations by year
- 2026: 1 · 2025: 7 · 2024: 4 · 2023: 7 · 2022: 9 · 2021: 5 · 2020: 8 · 2019: 10 · 2018: 7 · 2017: 8 · 2016: 10 · 2015: 13 · 2014: 14 · 2013: 19 · 2012: 11
- FWCI
- 8.31
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Funders
- Wellcome Trust
- Biotechnology and Biological Sciences Research Council (BBS/B/07683)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Physical Sciences › Chemistry › Inorganic Chemistry › Metal-Catalyzed Oxygenation Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- FIH, Notch receptor, ankyrin repeat domain, hypoxia-inducible factor, protein stability, oxygen sensing, protein-protein interaction, conformational change, crystal structure, Notch signaling
- MeSH terms
- Receptor, Notch3, Asparagine, Humans, Mixed Function Oxygenases, Hydroxylation, Repressor Proteins, Transcription Factors, Ankyrin Repeat, Protein Structure, Tertiary, Crystallography, X-Ray, Hypoxia-Inducible Factor 1, alpha Subunit, Receptors, Notch, Receptor, Notch1, Receptor, Notch2
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