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Publication

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

Cell reports | 2018

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.

Pubmed ID: 30232011 RIS Download

Research resources used in this publication

EA.hy 926 (RRID:CVCL_3901) (cell line)

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Antibodies used in this publication

Associated grants

Agency: NIGMS NIH HHS, United States
Id: R01 GM111665
Agency: NHLBI NIH HHS, United States
Id: R35 HL135737
Agency: NIAID NIH HHS, United States
Id: R01 AI118985
Agency: NIGMS NIH HHS, United States
Id: T32 GM007752
Agency: NIGMS NIH HHS, United States
Id: R35 GM127121
Agency: NINDS NIH HHS, United States
Id: R01 NS102432
Agency: NIGMS NIH HHS, United States
Id: R01 GM117424

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