The proliferative and antiapoptotic effects of substance P are facilitatedby formation of a beta-arrestin-dependent scaffolding complex

A requirement for scaffolding complexes containing internalized G protein-c oupled receptors and beta-arrestins in the activation and subcellular local ization of extracellular signal-regulated kinases 1 and 2 (ERK1/2) has rece ntly been proposed. However, the composition of these complexes and the imp ortance of this requirement for function of ERK1/2 appear to differ between receptors. Here we report that substance P (SP) activation of neurokinin-1 receptor (NK1R) stimulates the formation of a scaffolding complex comprisi ng internalized receptor, beta-arrestin, src. and ERK1/2 (detected by gel f iltration, immunoprecipitation, and immunofluorescence). Inhibition of comp lex formation, by expression of dominant-negative beta-arrestin or a trunca ted NK1R that fails to interact with beta-arrestin. inhibits both SP-stimul ated endocytosis of the NK1R and activation of ERK1/2 which is required for the proliferative and antiapoptotic effects of SP. Thus, formation of a be ta-arrestin-containing complex facilitates the proliferative and antiapopto tic effects of SP, and these effects of SP could be diminished in cells exp ressing truncated NK1R corresponding to a naturally occurring variant.