A requirement for scaffolding complexes containing internalized G protein-coupled receptors and ␤-arrestins in the activation and subcellular localization of extracellular signal-regulated kinases 1 and 2 (ERK1͞2) has recently been proposed. However, the composition of these complexes and the importance of this requirement for function of ERK1͞2 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 comprising internalized receptor, ␤-arrestin, src, and ERK1͞2 (detected by gel filtration, immunoprecipitation, and immunofluorescence). Inhibition of complex formation, by expression of dominant-negative ␤-arrestin or a truncated NK1R that fails to interact with ␤-arrestin, inhibits both SP-stimulated endocytosis of the NK1R and activation of ERK1͞2, which is required for the proliferative and antiapoptotic effects of SP. Thus, formation of a ␤-arrestin-containing complex facilitates the proliferative and antiapoptotic effects of SP, and these effects of SP could be diminished in cells expressing truncated NK1R corresponding to a naturally occurring variant.

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