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You searched for +publisher:"University of North Carolina" +contributor:("Trejo, JoAnn"). Showing records 1 – 3 of 3 total matches.

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University of North Carolina

1. Ricks, Tiffany K. Signal regulation of protease-activated receptor-2 and structural determinants of Gαq-dependent activation and deactivation of phospholipase C-β.

Degree: Pharmacology, 2010, University of North Carolina

Cells respond to changes in their environment by relaying information from extracellular cues to intracellular compartments, and receptors play an important role in the transmission of these signals. We examined signal transduction of G protein-coupled protease-activated receptor-2 (PAR2), a cell surface receptor for serine proteases. Unlike most GPCRs, PAR2 is irreversibly activated by proteolytic cleavage, and the mechanisms regulating desensitization and trafficking are essential for the fidelity of PAR2 signaling. Most activated GPCRs are rapidly desensitized and internalized following phosphorylation and β-arrestin binding. However, the role of phosphorylation in signaling and trafficking of PAR2 is unknown. We found that PAR2 phosphorylation is required for receptor desensitization and β-arrestin binding. Phosphorylated PAR2 internalized through a canonical dynamin-, clathrin-, and β-arrestin-dependent pathway. In contrast, phosphorylation-deficient PAR2 constitutively internalized through a dynamin-dependent but clathrin- and β-arrestin-independent pathway. Collectively, we show that phosphorylation of PAR2 is critical for β-arrestin binding and desensitization but not endocytic trafficking. Activated PAR2 and GPCRs catalyze GTP exchange on heterotrimeric G proteins. GTP-bound Gα subunits activate protein effectors including phospholipases C- β (PLC-β) isozymes. PLC-β isozymes are stimulated by Gαq and also accelerate GTP hydrolysis of on their activating G protein. The mechanisms that regulate Gαq-dependent activation and deactivation of PLC-β are not clearly understood. Inspection of a threedimensional crystal structure of the PLC-β3⋅Gαq complex revealed three novel contacts within the binding interface. A small region following the C2 domain of PLC-β3 inserts into the effector binding pocket of Gαq. Gαq also makes electrostatic interactions with a region preceding the C2 domain of PLC-β3. In addition, a loop between the third and fourth EF hands of PLC-β3 contacts the nucleotide binding pocket of Gαq. Mutation of this loop abrogated PLC-β3 GAP activity, and a GAP-deficient PLC-β3 mutant displayed a much slower rate of deactivation. Consequently, PLC activity was largely unchanged compared to rapid termination of wildtype PLC-β3. Our studies define the important domains within the PLC-β3/Gαq binding interface that are required for activation and deactivation of PLC-β isozymes. The studies presented herein describe the mechanisms regulating PAR2 and GPCRs at the cell surface and controlling PLC-β isozymes within intracellular compartments. Advisors/Committee Members: Ricks, Tiffany K., Harden, T. Kendall, Trejo, JoAnn, University of North Carolina at Chapel Hill.

Subjects/Keywords: School of Medicine; Department of Pharmacology

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

APA (6th Edition):

Ricks, T. K. (2010). Signal regulation of protease-activated receptor-2 and structural determinants of Gαq-dependent activation and deactivation of phospholipase C-β. (Thesis). University of North Carolina. Retrieved from https://cdr.lib.unc.edu/record/uuid:df095959-028b-4e36-a6bd-f67dbd401a26

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16th Edition):

Ricks, Tiffany K. “Signal regulation of protease-activated receptor-2 and structural determinants of Gαq-dependent activation and deactivation of phospholipase C-β.” 2010. Thesis, University of North Carolina. Accessed December 05, 2020. https://cdr.lib.unc.edu/record/uuid:df095959-028b-4e36-a6bd-f67dbd401a26.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7th Edition):

Ricks, Tiffany K. “Signal regulation of protease-activated receptor-2 and structural determinants of Gαq-dependent activation and deactivation of phospholipase C-β.” 2010. Web. 05 Dec 2020.

Vancouver:

Ricks TK. Signal regulation of protease-activated receptor-2 and structural determinants of Gαq-dependent activation and deactivation of phospholipase C-β. [Internet] [Thesis]. University of North Carolina; 2010. [cited 2020 Dec 05]. Available from: https://cdr.lib.unc.edu/record/uuid:df095959-028b-4e36-a6bd-f67dbd401a26.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Ricks TK. Signal regulation of protease-activated receptor-2 and structural determinants of Gαq-dependent activation and deactivation of phospholipase C-β. [Thesis]. University of North Carolina; 2010. Available from: https://cdr.lib.unc.edu/record/uuid:df095959-028b-4e36-a6bd-f67dbd401a26

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation


University of North Carolina

2. Russo, Angela. Delineating and Rationally Perturbing Signaling Mechanisms Involved in Metastasis.

Degree: Pharmacology, 2009, University of North Carolina

Metastasis is the dissemination of tumor cells from the primary locus of formation to other organs. During migration from the primary tumor, tumor cells need to traverse the vasculature, a process termed extravasation. Extravasation is a critical step in the metastatic cascade and nevertheless a poorly understood phenomenon. Endothelial cells form a barrier, which prevents cells and plasma constituents from moving into interstitial tissues. The disruption of the endothelial barrier leads to increased barrier permeability resulting in enhanced cancer cell extravasation. Protease-activated receptor-1 (PAR1) is a G protein-coupled receptor uniquely activated by proteases. PAR1 increases endothelial permeability when activated by the protease thrombin. Strikingly, PAR1 signaling can also mediate decreases in endothelial permeability when activated by activated protein C (APC), an anti-coagulant protease. In the first two chapters of this dissertation I examined the mechanism responsible for protease-selective signaling by PAR1. I specifically examined the effect of APC and thrombin on the activation of RhoA and Rac1 that differentially regulate endothelial permeability. In chapter 2 of this dissertation I also investigated whether compartmentalization of PAR1 in caveolae was critical for APC selective signaling and I demonstrated that caveolae are required for APC-selective signaling to Rac1 activation and endothelial barrier protection. Furthermore, in chapter 3 of this dissertation I asked whether APC protection from thrombin-induced increased permeability involved desensitization of PAR1. And I reported that APC induces PAR1 phosphorylation and desensitizes endothelial cells to thrombin. The metastatic process also requires degradation of extracellular matrices by proteases present in the tumor microenvironment, especially serine proteases. Inhibition of these proteases has remarkable therapeutic effects against tumor progression. Maspin is an atypical member of the family of serine proteases inhibitors. Maspin inhibits the serine protease urokinase activated plasminogen and suppresses tumor growth and metastasis. Interestingly, maspin is silenced by epigenetic mechanisms in cancer cells. In chapter 4 of my dissertation I used artificial transcription factors (ATFs) as a novel strategy to re-activate maspin in breast cancer cells. I showed that re-expression of maspin by ATFs leads to reduction of tumor growth and metastasis in an in vivo xenograft animal model. Advisors/Committee Members: Russo, Angela, Trejo, JoAnn.

Subjects/Keywords: School of Medicine; Department of Pharmacology

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

APA (6th Edition):

Russo, A. (2009). Delineating and Rationally Perturbing Signaling Mechanisms Involved in Metastasis. (Thesis). University of North Carolina. Retrieved from https://cdr.lib.unc.edu/record/uuid:c3d90edf-ce0e-4a44-9192-3711a65927df

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16th Edition):

Russo, Angela. “Delineating and Rationally Perturbing Signaling Mechanisms Involved in Metastasis.” 2009. Thesis, University of North Carolina. Accessed December 05, 2020. https://cdr.lib.unc.edu/record/uuid:c3d90edf-ce0e-4a44-9192-3711a65927df.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7th Edition):

Russo, Angela. “Delineating and Rationally Perturbing Signaling Mechanisms Involved in Metastasis.” 2009. Web. 05 Dec 2020.

Vancouver:

Russo A. Delineating and Rationally Perturbing Signaling Mechanisms Involved in Metastasis. [Internet] [Thesis]. University of North Carolina; 2009. [cited 2020 Dec 05]. Available from: https://cdr.lib.unc.edu/record/uuid:c3d90edf-ce0e-4a44-9192-3711a65927df.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Russo A. Delineating and Rationally Perturbing Signaling Mechanisms Involved in Metastasis. [Thesis]. University of North Carolina; 2009. Available from: https://cdr.lib.unc.edu/record/uuid:c3d90edf-ce0e-4a44-9192-3711a65927df

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation


University of North Carolina

3. Wolfe, Breann Louise. Clathrin-dependent Internalization of Protease-activated Receptor-1: Regulation by Ubiquitination and Epsin.

Degree: Pharmacology, 2007, University of North Carolina

Thrombin, the main effector protease of the coagulation cascade elicits its cellular effects via activation of a family of G-protein coupled receptors (GPCRs) called proteaseactivated receptors (PARs). PAR1, the prototype of this family, is expressed in cells in and around blood vessels and mediates thrombin elicited cellular responses that are essential for hemostasis and thrombosis, embryonic development, and cancer progression. Thrombin binds to and cleaves the amino-terminal exodomain of PAR1, thus exposing a newly formed amino-terminus that binds intramolecularly to the body of the receptor and causes transmembrane signaling. Due to the irreversible, proteolytic mechanism of PAR1 activation, processes that contribute to signal termination, including desensitization, internalization and downregulation, are critically important for thrombin-elicited cellular responses. PAR1 displays two modes of receptor trafficking. Constitutive PAR1 internalization is mediated by the adaptor protein complex-2 (AP2), but is independent of arrestins, and is important for resensitization of thrombin signaling. Activated PAR1 internalizes by a clathrin- and dynamin-dependent pathway that is independent of arrestins and AP2 and is then sorted directly to lysosomes for degradation, a process that is important for signal termination. Studies of mammalian and yeast GPCRs have demonstrated a role for ubiquitination in trafficking of GPCRs. A major focus of this dissertation was to understand the role of ubiquitination in PAR1 trafficking. We found that PAR1 is basally ubiquitinated and undergoes agonist-induced deubiquitination. Ubiquitination of PAR1 negatively regulates constitutive internalization and specifies a distinct clathrin adaptor requirement for activated receptor internalization. PAR1 ubiquitination appears to inhibit binding of AP2 to PAR1 and therefore helps to retain PAR1 at the cell surface. The clathrin adaptor protein epsin binds to activated and ubiquitinated PAR1 to mediate receptor internalization. A deubiquitinated form of the receptor is sorted to lysosomes by a ubiquitin-independent mechanism that requires sorting nexin-1. These studies reveal a novel function for ubiquitination in regulation of GPCR trafficking. Advisors/Committee Members: Wolfe, Breann Louise, Trejo, JoAnn.

Subjects/Keywords: School of Medicine; Department of Pharmacology

Record DetailsSimilar RecordsGoogle PlusoneFacebookTwitterCiteULikeMendeleyreddit

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

APA (6th Edition):

Wolfe, B. L. (2007). Clathrin-dependent Internalization of Protease-activated Receptor-1: Regulation by Ubiquitination and Epsin. (Thesis). University of North Carolina. Retrieved from https://cdr.lib.unc.edu/record/uuid:8025eff2-1695-4669-adf3-2b1d616efa1f

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Chicago Manual of Style (16th Edition):

Wolfe, Breann Louise. “Clathrin-dependent Internalization of Protease-activated Receptor-1: Regulation by Ubiquitination and Epsin.” 2007. Thesis, University of North Carolina. Accessed December 05, 2020. https://cdr.lib.unc.edu/record/uuid:8025eff2-1695-4669-adf3-2b1d616efa1f.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

MLA Handbook (7th Edition):

Wolfe, Breann Louise. “Clathrin-dependent Internalization of Protease-activated Receptor-1: Regulation by Ubiquitination and Epsin.” 2007. Web. 05 Dec 2020.

Vancouver:

Wolfe BL. Clathrin-dependent Internalization of Protease-activated Receptor-1: Regulation by Ubiquitination and Epsin. [Internet] [Thesis]. University of North Carolina; 2007. [cited 2020 Dec 05]. Available from: https://cdr.lib.unc.edu/record/uuid:8025eff2-1695-4669-adf3-2b1d616efa1f.

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

Council of Science Editors:

Wolfe BL. Clathrin-dependent Internalization of Protease-activated Receptor-1: Regulation by Ubiquitination and Epsin. [Thesis]. University of North Carolina; 2007. Available from: https://cdr.lib.unc.edu/record/uuid:8025eff2-1695-4669-adf3-2b1d616efa1f

Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation

.