Cell reports (Cambridge), 2016-03, Vol.14 (11), p.2745-2760
2016
Details
- Autor(en) / Beteiligte
- Titel
- Substrate-Trapped Interactors of PHD3 and FIH Cluster in Distinct Signaling Pathways
- Ist Teil von
- Cell reports (Cambridge), 2016-03, Vol.14 (11), p.2745-2760
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2016
- Link zum Volltext
- Quelle
- Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
- Beschreibungen/Notizen
- Amino acid hydroxylation is a post-translational modification that regulates intra- and inter-molecular protein-protein interactions. The modifications are regulated by a family of 2-oxoglutarate- (2OG) dependent enzymes and, although the biochemistry is well understood, until now only a few substrates have been described for these enzymes. Using quantitative interaction proteomics, we screened for substrates of the proline hydroxylase PHD3 and the asparagine hydroxylase FIH, which regulate the HIF-mediated hypoxic response. We were able to identify hundreds of potential substrates. Enrichment analysis revealed that the potential substrates of both hydroxylases cluster in the same pathways but frequently modify different nodes of signaling networks. We confirm that two proteins identified in our screen, MAPK6 (Erk3) and RIPK4, are indeed hydroxylated in a FIH- or PHD3-dependent mechanism. We further determined that FIH-dependent hydroxylation regulates RIPK4-dependent Wnt signaling, and that PHD3-dependent hydroxylation of MAPK6 protects the protein from proteasomal degradation. [Display omitted] •The proteomic screen for FIH and PHD3 substrates identifies numerous interactors•Potential substrates are enriched in numerous hypoxia-regulated pathways•FIH regulates RIPK4 kinase activity by direct hydroxylation•Hydroxylation of Pro25 by PHD3 regulates MAPK6 (Erk3) protein stability Using quantitative interaction proteomics, Rodriguez et al. identify numerous potential hydroxylase substrates clustering in hypoxia regulated pathways and show that hydroxylation of two of these substrates, MAPK6 (Erk3) and RIPK4, has consequences for cellular functions.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2211-1247eISSN: 2211-1247DOI: 10.1016/j.celrep.2016.02.043Titel-ID: cdi_doaj_primary_oai_doaj_org_article_00ee3bfef4a149938e0c86349229f870
- Format
- –
- Schlagworte
- Amino Acid Sequence, Amino Acids, Dicarboxylic - chemistry, Chromatography, High Pressure Liquid, HEK293 Cells, Humans, Hypoxia-Inducible Factor 1, alpha Subunit - chemistry, Hypoxia-Inducible Factor 1, alpha Subunit - metabolism, Hypoxia-Inducible Factor-Proline Dioxygenases - antagonists & inhibitors, Hypoxia-Inducible Factor-Proline Dioxygenases - genetics, Hypoxia-Inducible Factor-Proline Dioxygenases - metabolism, Immunoblotting, Immunoprecipitation, Mitogen-Activated Protein Kinase 6 - antagonists & inhibitors, Mitogen-Activated Protein Kinase 6 - metabolism, Mixed Function Oxygenases - chemistry, Mixed Function Oxygenases - genetics, Mixed Function Oxygenases - metabolism, Peptides - analysis, Peptides - chemistry, Protein Interaction Maps, Protein-Serine-Threonine Kinases - chemistry, Protein-Serine-Threonine Kinases - metabolism, Repressor Proteins - chemistry, Repressor Proteins - genetics, Repressor Proteins - metabolism, Resource, RNA Interference, RNA, Small Interfering - metabolism, Signal Transduction, Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization, Substrate Specificity, Ubiquitination