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

PMID: 30232011 (view PubMed database entry)
DOI: 10.1016/j.celrep.2018.08.061 (read at publisher's website )
PMCID: PMC6226018 (free full text version available)

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Neil J Grimsey, Rachan Narala, Cara C Rada, Sohum Mehta, Bryan S Stephens, Irina Kufareva, John Lapek, David J Gonzalez, Tracy M Handel, Jin Zhang, JoAnn Trejo,

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 P2Y<sub>1</sub> 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.

Cell Rep (Cell reports)
[2018, 24(12):3312-3323.e5]

Cited: 15 times

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