title: Regulation of Chemokine Signal Integration by Activator of G-Protein Signaling 4 (AGS4).
abstract: Activator of G-protein signaling 4 (AGS4)/G-protein signaling modulator 3 (Gpsm3) contains three G-protein regulatory (GPR) motifs, each of which can bind Gαi-GDP free of GβγWe previously demonstrated that the AGS4-Gαi interaction is regulated by seven transmembrane-spanning receptors (7-TMR), which may reflect direct coupling of the GPR-Gαi module to the receptor analogous to canonical Gαβγheterotrimer. We have demonstrated that the AGS4-Gαi complex is regulated by chemokine receptors in an agonist-dependent manner that is receptor-proximal. As an initial approach to investigate the functional role(s) of this regulated interaction in vivo, we analyzed leukocytes, in which AGS4/Gpsm3 is predominantly expressed, from AGS4/Gpsm3-null mice. Loss of AGS4/Gpsm3 resulted in mild but significant neutropenia and leukocytosis. Dendritic cells, T lymphocytes, and neutrophils from AGS4/Gpsm3-null mice also exhibited significant defects in chemoattractant-directed chemotaxis and extracellular signal-regulated kinase activation. An in vivo peritonitis model revealed a dramatic reduction in the ability of AGS4/Gpsm3-null neutrophils to migrate to primary sites of inflammation. Taken together, these data suggest that AGS4/Gpsm3 is required for proper chemokine signal processing in leukocytes and provide further evidence for the importance of the GPR-Gαi module in the regulation of leukocyte function.
authors.affiliation: Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina (W.G.R., M.B.-O., J.B.B.); and B-Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland (I.-Y.H., A.V., J.H.K.).
authors.forename: William G
authors.initials: WG
authors.lastname: Robichaux
authors.affiliation: Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina (W.G.R., M.B.-O., J.B.B.); and B-Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland (I.-Y.H., A.V., J.H.K.).
authors.forename: Melissa
authors.initials: M
authors.lastname: Branham-O'Connor
authors.affiliation: Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina (W.G.R., M.B.-O., J.B.B.); and B-Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland (I.-Y.H., A.V., J.H.K.).
authors.forename: Il-Young
authors.initials: IY
authors.lastname: Hwang
authors.affiliation: Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina (W.G.R., M.B.-O., J.B.B.); and B-Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland (I.-Y.H., A.V., J.H.K.).
authors.forename: Ali
authors.initials: A
authors.lastname: Vural
authors.affiliation: Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina (W.G.R., M.B.-O., J.B.B.); and B-Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland (I.-Y.H., A.V., J.H.K.).
authors.forename: Johne H
authors.initials: JH
authors.lastname: Kehrl
authors.affiliation: Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina (W.G.R., M.B.-O., J.B.B.); and B-Cell Molecular Immunology Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland (I.-Y.H., A.V., J.H.K.) blumerjb@musc.edu.
authors.forename: Joe B
authors.initials: JB
authors.lastname: Blumer
mesh_terms: D000818:Animals; D018925:Chemokines / Q000378:metabolism*; D002630:Chemotactic Factors / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D003713:Dendritic Cells / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000378:metabolism*; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D051379:Mice; D009504:Neutrophils / Q000502:physiology*; D020710:RGS Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013601:T-Lymphocytes / Q000502:physiology*
chemical_list: D018925:Chemokines; D002630:Chemotactic Factors; C548537:G18 protein, mouse; D020730:Guanine Nucleotide Dissociation Inhibitors; D020710:RGS Proteins; C098799:RGS4 protein; D048049:Extracellular Signal-Regulated MAP Kinases; D020962:Heterotrimeric GTP-Binding Proteins