1. Ubiquitin plays an atypical role in GPCR-induced p38 MAP kinase activation on endosomes.
- Author
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Grimsey NJ, Aguilar B, Smith TH, Le P, Soohoo AL, Puthenveedu MA, Nizet V, and Trejo J
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Adaptor Proteins, Signal Transducing metabolism, Animals, Capillary Permeability physiology, Endosomal Sorting Complexes Required for Transport genetics, Endosomal Sorting Complexes Required for Transport metabolism, Endosomes genetics, Endothelium, Vascular cytology, Endothelium, Vascular metabolism, HeLa Cells, Humans, Mice, Mice, Knockout, Nedd4 Ubiquitin Protein Ligases, Receptor, PAR-1 genetics, Ubiquitin genetics, Ubiquitin-Protein Ligases genetics, Ubiquitin-Protein Ligases metabolism, p38 Mitogen-Activated Protein Kinases genetics, Endosomes metabolism, MAP Kinase Signaling System physiology, Receptor, PAR-1 metabolism, Ubiquitin metabolism, Ubiquitination physiology, p38 Mitogen-Activated Protein Kinases metabolism
- Abstract
Protease-activated receptor 1 (PAR1) is a G protein-coupled receptor (GPCR) for thrombin and promotes inflammatory responses through multiple pathways including p38 mitogen-activated protein kinase signaling. The mechanisms that govern PAR1-induced p38 activation remain unclear. Here, we define an atypical ubiquitin-dependent pathway for p38 activation used by PAR1 that regulates endothelial barrier permeability. Activated PAR1 K63-linked ubiquitination is mediated by the NEDD4-2 E3 ubiquitin ligase and initiated recruitment of transforming growth factor-β-activated protein kinase-1 binding protein-2 (TAB2). The ubiquitin-binding domain of TAB2 was essential for recruitment to PAR1-containing endosomes. TAB2 associated with TAB1, which induced p38 activation independent of MKK3 and MKK6. The P2Y1 purinergic GPCR also stimulated p38 activation via NEDD4-2-mediated ubiquitination and TAB1-TAB2. TAB1-TAB2-dependent p38 activation was critical for PAR1-promoted endothelial barrier permeability in vitro, and p38 signaling was required for PAR1-induced vascular leakage in vivo. These studies define an atypical ubiquitin-mediated signaling pathway used by a subset of GPCRs that regulates endosomal p38 signaling and endothelial barrier disruption., (© 2015 Grimsey et al.)
- Published
- 2015
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