Endosomal GPCR signaling: Tyrosine Phosphorylation of a Peptide Linker in NEDD4‐2 Increases Ligase Activity to Promote p38 Proinflammatory Signaling

The regulation of G protein‐coupled receptor (GPCR) signaling is essential for vascular homeostasis and inflammatory responses during disease and injury. MAPK p38 is a key mediator of vascular inflammation, but how GPCRs regulate MAPK p38 signaling is relatively understudied. Post‐translational modi...

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Bibliographic Details
Published in:	The FASEB journal Vol. 32; no. S1; p. 687.10
Main Authors:	Grimsey, Neil J., Rada, Cara C., Narala, Rachan, Stephens, Bryan S., Mehta, Sohum J., Lapek, John J., Handel, Tracy M., Zhang, Jin J., Gonzalez, David J., Trejo, JoAnn
Format:	Journal Article
Language:	English
Published:	The Federation of American Societies for Experimental Biology 01-04-2018
Online Access:	Get full text
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Summary:	The regulation of G protein‐coupled receptor (GPCR) signaling is essential for vascular homeostasis and inflammatory responses during disease and injury. MAPK p38 is a key mediator of vascular inflammation, but how GPCRs regulate MAPK p38 signaling is relatively understudied. Post‐translational modifications play a key role in regulating spatiotemporal GPCR signaling and our studies have shown that ubiquitination of GPCRs is not just a cue for trafficking and degradation. Instead, GPCR ubiquitination plays a critical role in endosomal activation of an atypical MAPK p38 signaling pathway. Ubiquitinated receptors recruit the adaptor proteins TAB1 and TAB2 to endosomes and enable auto‐activation of p38, to induce proinflammatory signaling in the vasculature. We have shown that this pathway is conserved for GPCR activation by multiple proinflammatory agents in the vasculature including, thrombin, histamine, ADP and PGE2. Defining how GPCRs activate E3 ubiquitin ligases to initiate endosomal signaling is the focus of our current studies. Using FRET biosensors and phosphoproteomics studies we have discovered that GPCRs activate the E3 ubiquitin ligase NEDD4‐2 by c‐Src dependent tyrosine phosphorylation at a critical tyrosine residue (Tyr485). Tyr485 resides within a predicted auto‐inhibitory linker peptide between the protein binding domains WW II and WW III. Phosphorylation at Tyr485 is required for NEDD4‐2 activation, recruitment to GPCRs and the induction of ubiquitin dependent endosomal p38 signaling. Mutation of Tyr485 blocks thrombin and ADP induced p38 activity and significantly reduces thrombin mediated endothelial permeability. These studies are the first to define how NEDD4‐2 is activated by c‐Src tyrosine phosphorylation, and provides greater clarity into how GPCRs induce proinflammatory p38 signaling from endosomes. Future studies will critical for defining how to selectively block GPCR induced atypical p38 signaling. This is from the Experimental Biology 2018 Meeting. There is no full text article associated with this published in The FASEB Journal.
ISSN:	0892-6638 1530-6860
DOI:	10.1096/fasebj.2018.32.1_supplement.687.10