Differential regulation of Class IA Phosphatidylinositol 3-Kinase catalytic subunits p110alpha and beta by protease-activated-receptor-2 and beta-arrestins. [Biochem J] Journal article

Protease-activated receptor-2 (PAR-2) is a G-protein-coupled receptor that can elicit both G-protein- dependent and independent signals. We have previously shown that PAR-2 simultaneously promotes Galphaq/Ca 2+-dependent activation, and beta-arrestin-1-dependent-inhibition, of Class IA phosphoinositide 3-Kinase (PI3K), and we sought to further characterize the role of beta-arrestins in the regulation of PI3K activity. Whereas the ability of beta-arrestin-1 to inhibit p110alpha has been demonstrated, the role of beta-arrestin-2 in PI3K regulation and possible differences in the regulation of the two catalytic subunits associated with p85alpha (p110alpha and p110beta)have not been examined. Here, we demonstrate that: a) PAR-2 increases both p110alpha and p110beta-associated lipid kinase activities and both are inhibited by over-expression of either beta-arrestin-1 or 2; b) Both beta-arrestins directly inhibit the p110alpha catalytic subunit in vitro, whereas only beta-arrestin-2 directly inhibits p110beta; c) Examination of upstream pathways reveals that PAR-2 induced PI3K activity requires the small GTPase Cdc42, but not tyrosine phosphorylation of p85; and d) beta-arrestins inhibit PAR-2 induced Cdc42 activation. Taken together, these results indicate that beta-arrestins can inhibit PAR-2 stimulated PI3K activity both directly and through interference with upstream pathways, and that the two beta-arrestins differ in their ability to inhibit the p110alpha and beta catalytic subunits. These studies are particularly important in light of the growing interest in Protease-activated receptor-2 as a pharmacological target, as commonly used biochemical assays that monitor G-protein coupling would not screen for beta-arrestin-dependent signaling events.

Biochem J