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Substrate-Trapped Interactors of PHD3 and FIH Cluster in Distinct Signaling Pathways
Date Issued
2016-03-22
Date Available
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.
Sponsorship
European Commission - Seventh Framework Programme (FP7)
Science Foundation Ireland
University College Dublin
Other Sponsorship
Cancer Research UK
PRIMES Project
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
Language
English
Status of Item
Peer reviewed
This item is made available under a Creative Commons License
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Name
Substrate-Trapped Interactors of PHD3 and FIH Cluster.. GarciaA & TaylorC.pdf
Size
4.63 MB
Format
Adobe PDF
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