The proliferative and antiapoptotic effects of substance P are facilitated by formation of a beta -arrestin-dependent scaffolding complex.
A requirement for scaffolding complexes containing internalized G protein-coupled receptors and beta-arrestins in the activation and subcellular localization of extracellular signal-regulated kinases 1 and 2 (ERK1/2) has recently been proposed. However, the composition of these complexes and the importance 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 comprising internalized receptor, beta-arrestin, src, and ERK1/2 (detected by gel filtration, immunoprecipitation, and immunofluorescence). Inhibition of complex formation, by expression of dominant-negative beta-arrestin or a truncated NK1R that fails to interact with beta-arrestin, inhibits both SP-stimulated endocytosis of the NK1R and activation of ERK1/2, which is required for the proliferative and antiapoptotic effects of SP. Thus, formation of a beta-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.
DeFea
K A
KA
Department of Surgery, University of California, San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143-0660, USA.
Vaughn
Z D
ZD
O'Bryan
E M
EM
Nishijima
D
D
Déry
O
O
Bunnett
N W
NW
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D019390:Arrestins / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D020935:MAP Kinase Signaling System; D051381:Rats; D018040:Receptors, Neurokinin-1 / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects*; D013373:Substance P / Q000494:pharmacology*; D000071557:beta-Arrestins
D019390:Arrestins; D018040:Receptors, Neurokinin-1; D000071557:beta-Arrestins; D013373:Substance P