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J. Biol. Chem., Vol. 277, Issue 13, 10876-10882, March 29, 2002

This Article Full Text Full Text (PDF) All Versions of this Article: 277/13/10876    most recent M110397200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Graham, T. E. Articles by Dorin, R. I. Search for Related Content PubMed PubMed Citation Articles by Graham, T. E. Articles by Dorin, R. I. Social Bookmarking                      What's this?

Dexras1/AGS-1 Inhibits Signal Transduction from the G_i-coupled Formyl Peptide Receptor to Erk-1/2 MAP Kinases^*

Timothy E. Graham^§, Eric R. Prossnitz^¶, and Richard I. Dorin^§

From the  New Mexico Veterans Affairs Health Care System, Albuquerque, New Mexico 87108, the ^§ Departments of Internal Medicine and Biochemistry/Molecular Biology, and the ^¶ Department of Cell Biology and Physiology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico 87108

Dexras1 is a novel GTP-binding protein (G protein) that was recently discovered on the basis of rapid mRNA up-regulation by glucocorticoids in murine AtT-20 corticotroph cells and in several primary tissues. The human homologue of Dexras1, termed activator of G protein signaling-1 (AGS-1), has been reported to stimulate signaling by G_i heterotrimeric G proteins independently of receptor activation. The effects of Dexras1/AGS-1 on receptor-initiated signaling by G_i have not been examined. Here we report that Dexras1 inhibits ligand-dependent signaling by the G_i-coupled N-formyl peptide receptor (FPR). Dexras1 and FPR were transiently co-expressed in both COS-7 and HEK-293 cells. Activation of FPR by ligand (N-formyl-methionine-leucine-phenylalanine (f-MLF)) caused phosphorylation of endogenous Erk-1/2 that was reduced by co-expression of Dexras1. Direct effects of Dexras1 on the activity of co-expressed, epitope-tagged Erk-2 (hemagglutinin (HA)-Erk-2) were measured by immune complex in vitro kinase assay. Expression of Dexras1 alone resulted in a 1.9- to 4.9-fold increase in HA-Erk-2 activity; expression of the unliganded FPR alone resulted in a 6.2- to 8.1-fold increase in HA-Erk-2 activity. Stimulation of FPR by f-MLF produced a further 8- to 10-fold increase in HA-Erk-2 activity over the basal (non-ligand-stimulated) state, and this ligand-dependent activity was attenuated at the time points of maximal activity by co-expression of Dexras1 (reduced 31 ± 6.8% in COS-7 at 10 min and 86 ± 9.2% in HEK-293 at 5 min, p < 0.01 for each). Expression of Dexras1 did not influence protein expression of FPR or Erk, suggesting that the inhibitory effects of Dexras1 reflect a functional alteration in the signaling cascade from FPR to Erk. Expression of Dexras1 had no effect on expression of G_i species, but significantly impaired pertussis toxin-catalyzed ADP-ribosylation of membrane-associated G_i. Expression of Dexras1 also significantly decreased in vitro binding of GTPS in f-MLF-stimulated membranes of cells co-transfected with FPR. These data suggest that Dexras1 inhibits signal transduction from FPR to Erk-1/2 through an effect that is very proximal to receptor-G_i coupling. While Dexras1 weakly activates Erk in the resting state, more potent effects are evident in the modulation of ligand-stimulated receptor signal transduction, where Dexras1 functions as an inhibitor rather than activator of the Erk mitogen-activated protein kinase signaling cascade.

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