Substrate-Trapped Interactors of PHD3 and FIH Cluster in Distinct Signaling Pathways

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Title: Substrate-Trapped Interactors of PHD3 and FIH Cluster in Distinct Signaling Pathways
Authors: Rodriguez, Javier
Pilkington, Ruth
Garcia Munoz, Amaya
Nguyen, Lan K.
Rauch, Nora
Kennedy, Susan A.
Monsefi, Naser
Herrero, Ana
Taylor, Cormac T.
Kriegsheim, Alexander von
Permanent link: http://hdl.handle.net/10197/9754
Date: 22-Mar-2016
Online since: 2019-04-01T09:58:06Z
Abstract: 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.
Funding Details: European Commission - Seventh Framework Programme (FP7)
Science Foundation Ireland
University College Dublin
Type of material: Journal Article
Publisher: Elsevier
Journal: Cell Reports
Volume: 14
Issue: 11
Start page: 2745
End page: 2760
Copyright (published version): 2016 the Authors
Keywords: Hypoxiaregulated pathwaysFIHRIPK4 kinase activityHyroxylationPHD3MAPk6Erk3Quantitative interaction proteomicsCellular functionsDirect hydroxylation
DOI: 10.1016/j.celrep.2016.02.043
Language: en
Status of Item: Peer reviewed
Appears in Collections:SBI Research Collection

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