| First Author | Grimsey NJ | Year | 2015 |
| Journal | J Cell Biol | Volume | 210 |
| Issue | 7 | Pages | 1117-31 |
| PubMed ID | 26391660 | Mgi Jnum | J:227547 |
| Mgi Id | MGI:5701551 | Doi | 10.1083/jcb.201504007 |
| Citation | Grimsey NJ, et al. (2015) Ubiquitin plays an atypical role in GPCR-induced p38 MAP kinase activation on endosomes. J Cell Biol 210(7):1117-31 |
| abstractText | 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-beta-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. |
