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Papers In Press, published online ahead of print May 2, 2006
Department of Medicine, Medical University of South Carolina, Charleston, SC 29425
Corresponding Author: luttrell{at}musc.edu
The
J. Biol. Chem, 10.1074/jbc.M512643200
Submitted on November 28, 2005
Revised on April 26, 2006
Accepted on May 2, 2006
Constitutive ERK1/2 activation by a chimeric neurokinin NK1 receptor-
-arrestin1 fusion protein: Probing the composition and function of the G protein-coupled receptor 'signalsome'
-arrestins, a small family of G protein-coupled receptor (GPCR) binding proteins involved in receptor desensitization, have been shown to bind extracellular signal-regulated kinases 1 and 2 (ERK1/2) and function as scaffolds for GPCR-stimulated ERK1/2 activation. To better understand the mechanism -arrestin-mediated ERK1/2 activation, we compared ERK1/2 activation by the wild type Neurokinin 1 (NK1) receptor with a chimeric NK1 receptor having -arrestin1 fused to the receptor C-terminus (NK1-Arr1). The NK1 receptor couples to both Gs and Gq/11, resides primarily on the plasma membrane and mediates rapid ERK1/2 activation and nuclear translocation in response to neurokinin A (NKA). In contrast, NK1-Arr1 is a G protein-uncoupled 'constitutively desensitized' receptor that resides almost entirely in an intracellular endosomal compartment. Despite its inability to respond to NKA, we found that NK1-Arr1 expression caused robust constitutive activation of cytosolic ERK1/2 and that endogenous Raf, MEK1/2 and ERK1/2 coprecipitated in a complex with NK1-Arr1. While agonist-dependent ERK1/2 activation by the NK1 receptor was independent of Protein Kinase (PK)A or PKC activity, NK1-Arr1-mediated ERK1/2 activation was completely inhibited when basal PKA and PKC activity were blocked. In addition, the rate of ERK1/2 dephosphorylation was slowed in NK1-Arr1-expressing cells, suggesting that -arrestin-bound ERK1/2 is protected from Mitogen-Activated Protein Kinase Phosphatase activity. These data suggest that -arrestin binding to GPCRs nucleates the formation of a stable 'signalsome' that functions as a passive scaffold for the ERK1/2 cascade while confining ERK1/2 activity to an extra-nuclear compartment.
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