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University of Rochester

1. To, Jesi Lee Anne. The Importance of G Protein Signaling in Immune Cell Function: A Novel Role for Active Gαi in Cell Adhesion and Migration and the Therapeutic Potential of Targeting Gβγ in Inflammation.

Degree: PhD, 2020, University of Rochester

Chemotaxis is the directional movement of cells towards a gradient of chemoattractant such as chemokines. Chemokines are small peptides secreted by various cell types and play a role in immune surveillance, inflammation, and development. These molecules bind to their cognate receptors, which belong to the Class A, rhodopsin-like family of G protein-coupled receptors (GPCRs). Downstream effects orchestrated by chemokines include directional migration, reactive oxygen species (ROS) production, proliferation, and survival. Chemokine receptors primarily couple to the Gi/o family of Gα proteins. Their activation triggers dissociation of the heterotrimeric G protein, Gα and Gβγ dimer. The role of Gβγ in chemokine signaling is well established as it regulates multiple downstream effectors critical to cell migration such as phosphoinositide 3-kinase gamma (PI3Kγ), phosphatidylinositol 3,4,5-triphosphate-dependent Rac exchanger (P-Rex), p21 activated kinase/PAK-interacting exchange factor alpha (PAK/PIXα), and Ras-associating and diluted domain-containing protein (Radil). However, the role of Gαi in chemokine signaling is less understood and is thought to only regulate Gβγ availability and signaling through their association and disassociation cycle. Here we show that both Gαi-GTP and Gβγ signaling are pivotal to cell migration. We also provide evidence for a novel role of Gαi-GTP in regulating cell adhesion and migration. Using a small molecule inhibitor of Gβγ to inhibit migration, we show its anti-inflammatory therapeutic potential against lupus nephritis. Recently, our lab uncovered a novel role for Gαi-GTP signaling in neutrophil adhesion through a cAMP-independent pathway. To discover the mechanism for Gαi-GTP regulation of adhesion, we used a constitutively active Rap1a(G12V) and its downstream effector Radil to drive adhesion of neutrophil-like HL-60 and HT-1080 fibrosarcoma cells. A Gβγ-Rap1a-Radil complex is known to drive cell adhesion and migration of these cell types. We found that expression of constitutively active Gαi1(Q204L) reversed both Rap1a(G12V) and Radil mediated adhesion, suggesting that Gαi-GTP regulates adhesion downstream of Rap1a and Radil. Furthermore, Rap1a and Radil reduced migration of HT1080 cells, which is reversed by Gαi1(Q204L) expression. These data identify a novel role for Gαi-GTP in the regulation of cell adhesion and migration. Multiple chemokines play a role in propagating inflammation and are associated with lupus nephritis pathogenesis by orchestrating immune cell migration toward the kidneys. The chemokine/receptor system has vast and promiscuous properties as one chemokine can bind to multiple receptors and one receptor can bind to more than one ligand. Therefore, valid targeting of individual chemokine receptors associated with a disease may be challenging and display poor efficacy. We used a well-studied Gβγ inhibitor, gallein, to study its therapeutic potential in alleviating lupus nephritis. Gallein inhibited PI3Kγ-mediated PIP3 production in neutrophil-like HL-60 cells and…

Subjects/Keywords: Adhesion; Chemotaxis; G alpha i; G beta gamma; G protein; Migration.

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

To, J. L. A. (2020). The Importance of G Protein Signaling in Immune Cell Function: A Novel Role for Active Gαi in Cell Adhesion and Migration and the Therapeutic Potential of Targeting Gβγ in Inflammation. (Doctoral Dissertation). University of Rochester. Retrieved from http://hdl.handle.net/1802/35501

Chicago Manual of Style (16th Edition):

To, Jesi Lee Anne. “The Importance of G Protein Signaling in Immune Cell Function: A Novel Role for Active Gαi in Cell Adhesion and Migration and the Therapeutic Potential of Targeting Gβγ in Inflammation.” 2020. Doctoral Dissertation, University of Rochester. Accessed April 09, 2020. http://hdl.handle.net/1802/35501.

MLA Handbook (7th Edition):

To, Jesi Lee Anne. “The Importance of G Protein Signaling in Immune Cell Function: A Novel Role for Active Gαi in Cell Adhesion and Migration and the Therapeutic Potential of Targeting Gβγ in Inflammation.” 2020. Web. 09 Apr 2020.

Vancouver:

To JLA. The Importance of G Protein Signaling in Immune Cell Function: A Novel Role for Active Gαi in Cell Adhesion and Migration and the Therapeutic Potential of Targeting Gβγ in Inflammation. [Internet] [Doctoral dissertation]. University of Rochester; 2020. [cited 2020 Apr 09]. Available from: http://hdl.handle.net/1802/35501.

Council of Science Editors:

To JLA. The Importance of G Protein Signaling in Immune Cell Function: A Novel Role for Active Gαi in Cell Adhesion and Migration and the Therapeutic Potential of Targeting Gβγ in Inflammation. [Doctoral Dissertation]. University of Rochester; 2020. Available from: http://hdl.handle.net/1802/35501

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