Protease-activated receptor-2 simultaneously directs beta-arrestin-1-dependent inhibition and Galphaq-dependent activation of phosphatidylinositol 3-kinase.

Abstract

Protease-activated receptor-2 (PAR-2) is a G-protein-coupled receptor (GPCR) activated upon proteolytic cleavage of its N-terminus by a number of serine proteases. We have previously reported that formation of a beta-arrestin-dependent signaling scaffold is required for PAR-2-stimulated activation of extracellular signal regulated kinases 1 and 2 and chemotaxis. beta-Arrestin-dependent pathways downstream of some GPCRs have been shown to function independently and sometimes in opposition to classic signaling through heterotrimeric G-proteins; however, this possibility has not been addressed with respect to PAR-2. Here we demonstrate that PAR-2 can increase PI3K activity through a Galphaq/Ca(2+)-dependent pathway involving PYK2 and a Src-family kinase, while inhibiting PI3K activity through a beta-arrestin-dependent mechanism, and that beta-arrestin-1 can directly associate with and inhibit the catalytic activity of p110alpha. Using size exclusion chromatography and co-immunoprecipitation, we demonstrate that the PI3K is recruited into a scaffolding complex containing PAR-2 and beta-arrestins. Inhibition of PI3K activity blocks PAR-2-stimulated chemotaxis, and beta-arrestin-1 colocalizes with p85 within the pseudopodia, suggesting that beta-arrestin-1 association with PI3K may spatially restrict its enzymatic activity and that this localized inhibition may be crucial for PAR-2-stimulated chemotaxis.

Statistics

0501002008200920102011201220132014201520162017
Citations per Year

228 Citations

Semantic Scholar estimates that this publication has 228 citations based on the available data.

See our FAQ for additional information.

Cite this paper

@article{Wang2006ProteaseactivatedRS, title={Protease-activated receptor-2 simultaneously directs beta-arrestin-1-dependent inhibition and Galphaq-dependent activation of phosphatidylinositol 3-kinase.}, author={Ping Wang and Kathryn A Defea}, journal={Biochemistry}, year={2006}, volume={45 31}, pages={9374-85} }