A Tyrosine Switch on NEDD4-2 E3 Ligase Transmits GPCR Inflammatory Signaling

Cell Reports
Neil J GrimseyJoAnn Trejo

Abstract

Ubiquitination is essential for protein degradation and signaling and pivotal to many physiological processes. Ubiquitination of a subset of G-protein-coupled receptors (GPCRs) by the E3 ligase NEDD4-2 is required for p38 activation, but how GPCRs activate NEDD4-2 to promote ubiquitin-mediated signaling is not known. Here, we report that the GPCR protease-activated receptor-1 (PAR1) stimulates c-Src-mediated tyrosine phosphorylation and activation of NEDD4-2 to promote p38 signaling and endothelial barrier disruption. Using mass spectrometry, we identified a unique phosphorylated tyrosine (Y)-485 within the 2,3-linker peptide between WW domain 2 and 3 of NEDD4-2 in agonist-stimulated cells. Mutation of NEDD4-2 Y485 impaired E3 ligase activity and failed to rescue PAR1-stimulated p38 activation and endothelial barrier permeability. The purinergic P2Y1 receptor also required c-Src and NEDD4-2 tyrosine phosphorylation for p38 activation. These studies reveal a novel role for c-Src in GPCR-induced NEDD4-2 activation, which is critical for driving ubiquitin-mediated p38 inflammatory signaling.

Citations

Oct 4, 2019·The Journal of Biological Chemistry·Hanjie JiangPhilip A Cole
Mar 5, 2020·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Barry J Thompson
Apr 16, 2019·Frontiers in Cell and Developmental Biology·Jeremy C Burton, Neil J Grimsey
Apr 20, 2019·Frontiers in Physiology·Janine WeberElena Maspero
Feb 20, 2020·Proceedings of the National Academy of Sciences of the United States of America·Ying LinJoAnn Trejo
Jan 21, 2021·Biochemistry·Hanjie JiangPhilip A Cole
Aug 25, 2020·Current Opinion in Endocrine and Metabolic Research·Cierra A BirchJoAnn Trejo
May 1, 2021·International Journal of Molecular Sciences·Jeremy C BurtonNeil J Grimsey
Jul 24, 2021·Communications Biology·Pavel PohlVeronika Obsilova
Sep 2, 2021·Antioxidants & Redox Signaling·Helen WedegaertnerJoAnn Trejo
Sep 4, 2021·Proceedings of the National Academy of Sciences of the United States of America·Hyung-Seok KimJan L Christian

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Datasets Mentioned

BETA
MSV000081998

Methods Mentioned

BETA
ubiquitination
confocal microscopy
biosensors
FRET
biosensor
transfections
immunoprecipitations

Key Resources (RRID) Mentioned

AB_832813
AB_628423
AB_2279038
AB_2263416
AB_2279044
AB_131681
AB_439685
AB_476692
AB_1904063
AB_2140247

Software Mentioned

ImageJ
Pro
SequestHT
Prism
ProteomeDiscoverer
ICM
MetaMorph
MetaFluor

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