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Composition and function of G protein-coupled receptor signalsomes controlling mitogen-activated protein kinase activity

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Abstract

Seven membrane-spanning G protein-coupled receptors (GPCRs) function as ligand-activated guanine nucleotide exchange factors for heterotrimeric guanine nucleotide-binding (G) proteins that relay extracellular stimuli by activating intracellular effector enzymes or ion channels. Recent work, however, has shown that GPCRs also participate in numerous other protein-protein interactions that generate intracellular signals in conjunction with, or even independent of, G-protein activation. Nowhere has the importance of protein complex assembly in GPCR signaling been demonstrated more clearly than in the control of the spatial and temporal activity of the extracellular signal-regulated kinase (ERK1/2) mitogen-activated protein (MAP) kinase cascade. ERK1/2 activation by GPCRs often involves cross talk with classical receptor tyrosine kinases or focal adhesion complexes, which scaffold the assembly of a Ras activation complex. Even more surprising is the phenomenon of G protein-independent signaling using β-arrestins, proteins originally characterized for their role in homologous GPCR desensitization, as scaffolds for the assembly of a multiprotein signalsome directly upon the GPCR. Although both forms of signaling lead to MAP kinase activation, the pathways appear to be functionally, as well as mechanistically, distinct. Transactivated receptor tyrosine kinase mediate rapid and transient MAP kinase activation that favors nuclear translocation of the kinases and transcriptional activation. In contrast, β-arrestin-dependent signaling produces a slower and more sustained increase in MAP kinase activity that is often restricted to the cytosol. Together, these highly organized signaling complexes dictate the location, duration, and ultimate function of GPCR-stimulated MAP kinase activity.

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  1. Departments of Medicine and Biochemistry and Molecular Biology, Medical University of South Carolina, 29425, Charleston, SC

    Louis M. Luttrell

  2. The Ralph H. Johnson Veterans Affairs Medical Center, 29401, Charleston, SC

    Louis M. Luttrell

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Luttrell, L.M. Composition and function of G protein-coupled receptor signalsomes controlling mitogen-activated protein kinase activity. J Mol Neurosci 26, 253–264 (2005). https://doi.org/10.1385/JMN:26:2-3:253

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