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J. Biol. Chem., Vol. 279, Issue 26, 27567-27574, June 25, 2004

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Identification and Characterization of AGS4

A PROTEIN CONTAINING THREE G-PROTEIN REGULATORY MOTIFS THAT REGULATE THE ACTIVATION STATE OF G_i^*

Xiaoqing Cao, Mary J. Cismowski, Motohiko Sato, Joe B. Blumer, and Stephen M. Lanier¶

From the The Guthrie Research Institute, Sayre, Pennsylvania 18840 and the Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, Louisiana 70112

Activators of G-protein signaling 1-3 (AGS1-3) were identified in a functional screen of mammalian cDNAs that activated G-protein signaling in the absence of a receptor. We report the isolation and characterization of an additional AGS protein (AGS4) from a human prostate leiomyosarcoma cDNA library. AGS4 is identical to G18.1b, which is encoded by a gene within the major histocompatibility class III region of chromosome 6. The activity of AGS4 in the yeast-based functional screen was selective for G_i2/G_i3 and independent of guanine-nucleotide exchange by G_i. RNA blots indicated enrichment of AGS4/G18.1b mRNA in heart, placenta, lung, and liver. Immunocytochemistry with AGS4/G18.1b-specific antisera indicated a predominant nonhomogeneous, extranuclear distribution within the cell following expression in COS7 or Chinese hamster ovary cells. AGS4/G18.1b contains three G-protein regulatory motifs downstream of an amino terminus domain with multiple prolines. Glutathione S-transferase (GST)-AGS4/G18.1b fusion proteins interacted with purified G_i, and peptides derived from each of the G-protein regulatory motifs inhibited guanosine 5'-3-O-(thio)triphosphate (GTPS) binding to purified G_i1. AGS4/G18.1b was also complexed with G_i3 in COS7 cell lysates following cell transfection. However, AGS4/G18.1b did not alter the generation of inositol phosphates in COS7 cells cotransfected with the G-regulated effector phospholipase C-2. These data suggest either that an additional signal is required to position AGS4/G18.1b in the proper cellular location where it can access heterotrimer and promote subunit dissociation or that AGS4 serves as an alternative binding partner for G_i independent of G participating in G-protein signaling events that are independent of classical G-protein-coupled receptors at the cell surface.

Received for publication, November 21, 2003 , and in revised form, April 16, 2004.

^* This work was supported by National Institutes of Health Grants MH90531 (to S. M. L.), NS24821 (to S. M. L.), and F32MH65092 (to J. B. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ Supported by the David R. Bethune/Lederle Laboratories Professorship in Pharmacology and the Research Scholar Award from Yamanouchi Pharmaceutical Company, Ltd. To whom correspondence should be addressed: Dept. of Pharmacology, LSUHSC, 1901 Perdido St., New Orleans, LA 70112. Tel.: 504-568-4740; E-mail: slanie{at}lsuhsc.edu.

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