Substrate-Trapped Interactors of PHD3 and FIH Cluster in Distinct Signaling Pathways
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 substra...
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2016-03-01
|
| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124716301462 |
| _version_ | 1819133250176548864 |
|---|---|
| author | Javier Rodriguez Ruth Pilkington Amaya Garcia Munoz Lan K. Nguyen Nora Rauch Susan Kennedy Naser Monsefi Ana Herrero Cormac T. Taylor Alex von Kriegsheim |
| author_facet | Javier Rodriguez Ruth Pilkington Amaya Garcia Munoz Lan K. Nguyen Nora Rauch Susan Kennedy Naser Monsefi Ana Herrero Cormac T. Taylor Alex von Kriegsheim |
| author_sort | Javier Rodriguez |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T09:44:18Z |
| format | Article |
| id | doaj.art-00ee3bfef4a149938e0c86349229f870 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-22T09:44:18Z |
| publishDate | 2016-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-00ee3bfef4a149938e0c86349229f8702022-12-21T18:30:35ZengElsevierCell Reports2211-12472016-03-0114112745276010.1016/j.celrep.2016.02.043Substrate-Trapped Interactors of PHD3 and FIH Cluster in Distinct Signaling PathwaysJavier Rodriguez0Ruth Pilkington1Amaya Garcia Munoz2Lan K. Nguyen3Nora Rauch4Susan Kennedy5Naser Monsefi6Ana Herrero7Cormac T. Taylor8Alex von Kriegsheim9Systems Biology Ireland, University College Dublin, Dublin 4, IrelandSystems Biology Ireland, University College Dublin, Dublin 4, IrelandSystems Biology Ireland, University College Dublin, Dublin 4, IrelandSystems Biology Ireland, University College Dublin, Dublin 4, IrelandSystems Biology Ireland, University College Dublin, Dublin 4, IrelandSystems Biology Ireland, University College Dublin, Dublin 4, IrelandSystems Biology Ireland, University College Dublin, Dublin 4, IrelandSystems Biology Ireland, University College Dublin, Dublin 4, IrelandSystems Biology Ireland, University College Dublin, Dublin 4, IrelandSystems Biology Ireland, University College Dublin, Dublin 4, IrelandAmino 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.http://www.sciencedirect.com/science/article/pii/S2211124716301462 |
| spellingShingle | Javier Rodriguez Ruth Pilkington Amaya Garcia Munoz Lan K. Nguyen Nora Rauch Susan Kennedy Naser Monsefi Ana Herrero Cormac T. Taylor Alex von Kriegsheim Substrate-Trapped Interactors of PHD3 and FIH Cluster in Distinct Signaling Pathways Cell Reports |
| title | Substrate-Trapped Interactors of PHD3 and FIH Cluster in Distinct Signaling Pathways |
| title_full | Substrate-Trapped Interactors of PHD3 and FIH Cluster in Distinct Signaling Pathways |
| title_fullStr | Substrate-Trapped Interactors of PHD3 and FIH Cluster in Distinct Signaling Pathways |
| title_full_unstemmed | Substrate-Trapped Interactors of PHD3 and FIH Cluster in Distinct Signaling Pathways |
| title_short | Substrate-Trapped Interactors of PHD3 and FIH Cluster in Distinct Signaling Pathways |
| title_sort | substrate trapped interactors of phd3 and fih cluster in distinct signaling pathways |
| url | http://www.sciencedirect.com/science/article/pii/S2211124716301462 |
| work_keys_str_mv | AT javierrodriguez substratetrappedinteractorsofphd3andfihclusterindistinctsignalingpathways AT ruthpilkington substratetrappedinteractorsofphd3andfihclusterindistinctsignalingpathways AT amayagarciamunoz substratetrappedinteractorsofphd3andfihclusterindistinctsignalingpathways AT lanknguyen substratetrappedinteractorsofphd3andfihclusterindistinctsignalingpathways AT norarauch substratetrappedinteractorsofphd3andfihclusterindistinctsignalingpathways AT susankennedy substratetrappedinteractorsofphd3andfihclusterindistinctsignalingpathways AT nasermonsefi substratetrappedinteractorsofphd3andfihclusterindistinctsignalingpathways AT anaherrero substratetrappedinteractorsofphd3andfihclusterindistinctsignalingpathways AT cormacttaylor substratetrappedinteractorsofphd3andfihclusterindistinctsignalingpathways AT alexvonkriegsheim substratetrappedinteractorsofphd3andfihclusterindistinctsignalingpathways |