Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 97, Issue 20, Pages 11086-11091Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.190276697
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- NIDDK NIH HHS [R01 DK039957, DK39957, R37 DK039957] Funding Source: Medline
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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.
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