Joe Blumer, PhD
Member, Developmental Cancer Therapeutics Program
Hollings Cancer Center
2000 Ph.D., Emory University
Office: STB 302
Role of G-protein Regulatory (GPR) Proteins in Mammalian Cell Division and the Immune System
Heterotrimeric GTP-binding proteins (G-proteins) are perhaps the most widely used proteins in cellular communication, mediating cellular responses to an extraordinary variety of hormones and neurotransmitters. The recent discovery of accessory proteins that serve as alternative binding partners to heterotrimeric G-proteins implicates functional roles for G-proteins distinct from “traditional” receptor-G protein-effector signaling systems. Thus, novel roles for G-protein signaling on cellular control mechanisms governing cell division, cell polarity and differentiation are now being appreciated.
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, which contain the G-protein regulatory (GPR) motif and include AGS3, AGS4 and AGS5/LGN, play central regulatory roles in cell division, neuronal development, synaptic plasticity, the biology of addiction, energy homeostasis, and cardiovascular functions, thus underlying their importance as G-protein signal modulators. Currently there are two ongoing projects in my lab.
1) Role of G-protein Regulatory (GPR) Proteins in Mammalian Cell Division
Interestingly, AGS3/LGN orthologs and related proteins in conjunction with heterotrimeric G-proteins are essential for asymmetric cell division in model organisms Drosophila and C. elegans. Initial experiments have explored the roles of these proteins in conjunction with G-proteins during mammalian cell division. We recently identified AGS3, LGN and Giα in spindle poles of dividing cells, and the altered expression of these proteins results in defects in spindle pole positioning. Our working hypothesis is that LGN and G-proteins are involved in the relay of information between spindle pole and cortex that is critical for proper spindle pole positioning and mitotic spindle orientation.
As part of a broader effort to determine a functional role for AGS3 in vivo, I have generated a conditional AGS3 knockout mouse strain using a Cre/Lox approach. A first phase of phenotyping includes cardiovascular, behavioral, and metabolic profiling. Studies to assess overall changes in adult brain region morphology and cellularity are currently underway. The development of the AGS3 knockout mouse model provides a broad platform for discovery of the role of AGS3 in the intact animal and also begins to define the in vivo relationship between AGS3 and G-protein signaling and will likely lead to generation of new hypotheses regarding AGS3 and signal processing through heterotrimeric G-proteins. The discovery of AGS3 and related accessory proteins may provide novel therapeutic targets and may uncover roles for their involvement in the pathophysiology of disease.
2) Roles for GPR Proteins in the Immune System
The long-term objectives of this project effort are: (1) to characterize and determine the functional role of the previously unknown GPR protein, AGS4, which provides a platform for (2) to determine functional roles for GPR proteins AGS3-5 in the immune system. With respect to defining a functional role for AGS4, there are many directions which can be pursued, but given the expression profile of AGS4 our initial studies are focused on the immune system.
AGS4 is of particular interest in this context given that its expression is essentially restricted to immune cells. In addition, nothing is known regarding the regulation of AGS4 expression, subcellular distribution, its binding partners, its interaction with G-protein or its influence on chemokine receptor signaling. Nearly all of the chemokine and chemoattractant receptors on lymphoid cells are GPCRs which couple to the Giα class of heterotrimeric G-proteins. Giα plays a critical role in lymphocyte biology and the immune response, and factors that modulate its activity will provide a more precise understanding of how lymphocytes integrate the myriad chemokine signals they receive into an effective immune response and may lead to the discovery of novel therapeutics. AGS3-5, by virtue of their ability to influence G-protein signal processing, are in a unique position to modulate G-protein signal processing of diverse stimuli critical for immune cell function.
Overall Hypothesis: Regulated interaction of AGS3-5 with Giα subunits in lymphoid cells modulates lymphocyte trafficking, maturation, and activation.
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 reveal potential targets for therapeutics for diseases which result from altered heterotrimeric G-protein signaling. Defects in chemokine and chemoattractant signaling can lead to alterations in lymphoid cell trafficking and/or activation which is the basis for many immune system disorders. Immune cell specific GPR proteins like AGS4 are in an ideal position to modulate chemokine-specific G-protein signaling and investigating its role in this context will reveal additional mechanisms controlling the “G-switch” to influence lymphocyte signaling and responses to chemokines.
Recent Publications | Additional Publications
1. Vellano, C.P., Brown, N.E., Blumer, J.B., and Hepler, J.R. Regulator of G Protein Signaling 14 (RGS14) Interaction with H-Ras in Live Cells is Regulated by Gαi1 and a Gαi-linked G Protein-Coupled Receptor. J. Biol. Chem. (2012) (in press)
2. Kwon, M., Nozu, K., Pavlov, T., Rasmussen, S., Gaggl-Lerch, A., Qian, F., Sweeney, Jr., W.E., Avener, E., Blumer, J.B., Staruschenko, A., and Park, F. G-protein signaling modulator 1 deficiency accelerates cyst progression in an orthologous mouse model of ADPKD. Proc. Natl. Acad. Sci. (2012) (in press)
3. Oner, S.S., Maher, E.M., Blumer, J.B.*, Lanier, S.M.* Regulation of the GPR-Gai Signaling Complex by a Non-Receptor Guanine Nucleotide Exchange Factor, RIC-8A. *Co-Senior Authors J. Biol. Chem. (2012) (in press)
4. Blumer, J.B. and Tall, G.G. Gai/o/z proteins. Encyclopedia of Signaling Molecules. (2012) (in press)
5. Oner, S.S., Blumer, J.B. and Lanier, S.M. Group II Activators of G-protein Signaling: Regulation of the interaction of Ga with the G-protein Regulatory Motif. Methods in Enzymology. (invited review) (2012) (in press).
6. Blumer, J.B., Oner, S.S., and Lanier, S.M. Group II Activators Of G-Protein Signaling and Proteins Containing a G-Protein Regulatory Motif. Acta Physiologica 204(2):202-18. (2012) (Invited Review)
7. Vellano, C.P., Maher, E.M., Hepler, J.R., and Blumer, J.B. G Protein-coupled Receptors and Resistance to Inhibitors of Cholinesterase 8A (Ric-8A), Both, Regulate the Regulator of G Protein Signaling 14 (RGS14)•Gai1 Complex in Live Cells. J. Biol. Chem. 286(44):38659-69. (2011)
8. Regner, K.R., Nozu, K., Lanier, S.M., Blumer, J.B., Avner, E.D., Sweeney, Jr., W.E., Park, F. Loss of Activator of G Protein Signaling 3 Impairs Renal Tubular Regeneration Following Acute Kidney Injury in Rodents. FASEB J. Jun;25(6):1844-55. (2011)
9. Reissner, K.J., Uys, J.D., Schwacke, J.H., Comte-Walters, S., Rutherford-Bethard, J., Dunn, T.E., Blumer, J.B., Schey, K.L, and Kalivas, P.W. AKAP Signaling in Reinstated Cocaine Seeking Revealed by iTRAQ Proteomic Analysis. J. Neurosci. 31(15):5648-58. (2011)
10. Gabay, M., Chan, P.Y., Wright, F.A., Kan, W., Oner, S.S., Lanier, S.M., Smrcka, A.V., Blumer, J.B., Tall, G.G. Purification Of Heterotrimeric G Protein a Subunits By Ric-8 Affinity: Characterization Of GaOlf. J. Biol. Chem. 286(4):2625-35. (2011)
11. Oner, S.S., Maher, E.M., Breton, B., Bouvier, M. and Blumer, J.B. Receptor-Regulated Interaction of Activator of G-Protein Signaling 4 And Gialpha. J. Biol. Chem. 285:20588-94. (2010)
12. Oner, S.S., An, N., Vural, A., Breton, B., Bouvier, M., Blumer, J.B. and Lanier, S.M. Regulation of the AGS3-Gαi Signaling Complex by a Seventransmembrane Span Receptor. J. Biol. Chem. 285(44):33949-58. (2010)