Abstract

Activator of G-protein Signaling (AGS) proteins provide alternate modes of signal input to heterotrimeric G- proteins and diversify G-protein signaling through unexpected mechanisms. Group II AGS proteins contain 1-4 G-protein regulatory (GPR) motifs that serve as a docking site for Gi1-GDP free of G23. Group II AGS proteins include AGS3 and AGS5/LGN, which play important regulatory roles in cell division, neuronal development, synaptic plasticity, the biology of addiction, energy homeostasis, and cardiovascular functions. A long-term objective of this research effort is to determine the functional role of the Group II AGS protein AGS4 in regulating G-protein signaling with a specific focus on the immune system where AGS4 is enriched in lymphocytes. As the first approach to this longer term objective, this proposal addresses key questions related to the interaction of AGS4 with G-proteins and the impact of this interaction on signal processing in the cell.
Specific aim #1 Determine the factors and mechanisms that influence AGS4 interaction with Gi1 subunits to test the hypothesis that the AGS4-Gi1 interaction is a regulated event.
Specific aim #2 Determine the factors that influence the subcellular distribution of AGS4 to test the hypothesis that positioning of AGS4 is regulated and influences its interaction with G-protein.
Specific aim #3 Determine the effect of altered AGS4 levels on G-protein signaling in S1A and Jurkat T cells to test the hypothesis that AGS4 modulates GPCR - G-protein signal processing. Group II AGS proteins like AGS4 provide insight into novel modes of signal input and regulation of heterotrimeric G-protein signaling and provide a platform for discovering mechanisms underlying signal strength, specificity, and integration of G-protein mediated cellular responses. Furthermore, they provide unexpected targets for development of therapeutics for diseases which result from altered heterotrimeric G-protein signaling.

Public Health Relevance

The work proposed in this application focuses on basic mechanisms for regulation of a major system that controls function of various tissues in the body including the immune system. The area of investigation has merit from the perspective of disease diagnostics and the development of new therapeutic strategies.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM086510-03
Application #
8078159
Study Section
Molecular and Integrative Signal Transduction Study Section (MIST)
Program Officer
Dunsmore, Sarah
Project Start
2009-08-01
Project End
2014-05-31
Budget Start
2011-06-01
Budget End
2012-05-31
Support Year
3
Fiscal Year
2011
Total Cost
$302,803
Indirect Cost

  Institution

Name
Medical University of South Carolina
Department
Pharmacology
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425

  Publications

Robichaux 3rd, William G; Branham-O'Connor, Melissa; Hwang, Il-Young et al. (2017) Regulation of Chemokine Signal Integration by Activator of G-Protein Signaling 4 (AGS4). J Pharmacol Exp Ther 360:424-433
Robichaux 3rd, William G; Oner, Sukru S; Lanier, Stephen M et al. (2015) Direct Coupling of a Seven-Transmembrane-Span Receptor to a G?i G-Protein Regulatory Motif Complex. Mol Pharmacol 88:231-7
Blumer, Joe B; Lanier, Stephen M (2014) Activators of G protein signaling exhibit broad functionality and define a distinct core signaling triad. Mol Pharmacol 85:388-96
Bradley, Amber; Zheng, Hui; Ziebarth, Angela et al. (2014) EDD enhances cell survival and cisplatin resistance and is a therapeutic target for epithelial ovarian cancer. Carcinogenesis 35:1100-9
Oner, Sukru Sadik; Blumer, Joe B; Lanier, Stephen M (2013) Group II activators of G-protein signaling: monitoring the interaction of Gýý with the G-protein regulatory motif in the intact cell. Methods Enzymol 522:153-67
Vellano, Christopher P; Brown, Nicole E; Blumer, Joe B et al. (2013) Assembly and function of the regulator of G protein signaling 14 (RGS14)·H-Ras signaling complex in live cells are regulated by G?i1 and G?i-linked G protein-coupled receptors. J Biol Chem 288:3620-31
Oner, Sukru Sadik; Maher, Ellen M; Gabay, Meital et al. (2013) Regulation of the G-protein regulatory-G?i signaling complex by nonreceptor guanine nucleotide exchange factors. J Biol Chem 288:3003-15
Kwon, Michelle; Pavlov, Tengis S; Nozu, Kandai et al. (2012) G-protein signaling modulator 1 deficiency accelerates cystic disease in an orthologous mouse model of autosomal dominant polycystic kidney disease. Proc Natl Acad Sci U S A 109:21462-7
Blumer, J B; Oner, S S; Lanier, S M (2012) Group II activators of G-protein signalling and proteins containing a G-protein regulatory motif. Acta Physiol (Oxf) 204:202-18
Chan, PuiYee; Gabay, Meital; Wright, Forrest A et al. (2011) Purification of heterotrimeric G protein alpha subunits by GST-Ric-8 association: primary characterization of purified G alpha(olf). J Biol Chem 286:2625-35

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