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Ligand-induced selective signalling at the gonadotrophin releasing hormone receptor
Includes abstract.
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| Other Authors: | |
| Format: | Thesis |
| Language: | English |
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Division of Medical Biochemistry
2014
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| _version_ | 1867613186812805120 |
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| access_status_str | Open Access |
| author | Coetsee, Marla Catherine |
| author2 | Flanagan, Colleen |
| author_browse | Coetsee, Marla Catherine Flanagan, Colleen |
| author_facet | Flanagan, Colleen Coetsee, Marla Catherine |
| author_sort | Coetsee, Marla Catherine |
| collection | Thesis |
| description | Includes abstract. |
| format | Thesis |
| id | oai:open.uct.ac.za:11427/3123 |
| institution | University of Cape Town (South Africa) |
| language | eng |
| last_indexed | 2026-06-10T12:32:08.355Z |
| license_str | Not specified — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UCTD — University of Cape Town Open Access Repository |
| publishDate | 2014 |
| publishDateRange | 2014 |
| publishDateSort | 2014 |
| publisher | Division of Medical Biochemistry |
| publisherStr | Division of Medical Biochemistry |
| record_format | dspace |
| source_str | UCTD — University of Cape Town Open Access Repository |
| spelling | oai:open.uct.ac.za:11427/3123 Ligand-induced selective signalling at the gonadotrophin releasing hormone receptor Coetsee, Marla Catherine Flanagan, Colleen Medical Biochemistry Includes abstract. Includes bibliographical references (p. 179-202). The pituitary gonadotrophin releasing hormone (GnRH) receptor regulates reproduction by activation of Gq/11 proteins. In contrast, GnRH receptors at extrapituitary sites induce anti-proliferative effects that do not correlate with Gq/11 activation. We propose that the two endogenous ligands, GnRH I and GnRH II, and certain antagonists selectively activate distinct signalling pathways by stabilisation of distinct active conformations of the GnRH receptor, a concept termed ligand-induced selective signalling (LiSS). This dissertation has investigated LiSS at the GnRH receptor using several approaches. The sequences of GnRH I and II differ in positions 5, 7 and 8. I investigated the interaction of position 5 of GnRH I and GnRH II with Tyr6.58 of the receptor. Compared with the Leu and Ala mutants, the Tyr6.58Phe mutant had higher affinity for native GnRHs, but not Ala5-substituted GnRHs, suggesting that Tyr5 of GnRH I and His5 of GnRH II interact with Tyr6.58 by aromatic interactions. Our molecular models show that GnRHs interact with distinct rotamer conformations of Tyr6.58. This is supported by the Tyr6.58Leu receptor, which makes compensatory interactions that improve binding affinity and receptor activation for GnRH II, but not GnRH I, compared with the Tyr6.58Ala receptor. Together these results suggest that GnRHs stabilise distinct receptor active conformations. To identify the most proximal signalling proteins that mediate GnRH receptordependent anti-proliferative effects, I established a range of [35S]GTPS binding assays. I confirmed that the GnRH receptor activates Gq/11, but in contrast to previous proposals, my results show that the GnRH receptor cannot directly activate Gi. I subsequently identified a novel GnRH receptor signalling partner, the SH2 domaincontaining phosphatase 2 (SHP-2). I propose that SHP-2 mediates the antiproliferative effects of the receptor. I show that the SHP-2 pathway is activated independently of Gq/11 and suggest that signalling occurs by a direct interaction of SHP-2 and src with the GnRH receptor. Furthermore, this pathway is activated by a classical Gq/11 antagonist or by Gq/11-uncoupled GnRH receptor mutants. My results provide convincing evidence supporting LiSS at the GnRH receptor and may facilitate development of therapeutics with increased signalling specificity at this receptor. 2014-07-28T14:54:47Z 2014-07-28T14:54:47Z 2008 Doctoral Thesis Doctoral PhD http://hdl.handle.net/11427/3123 eng application/pdf Division of Medical Biochemistry Faculty of Health Sciences University of Cape Town |
| spellingShingle | Medical Biochemistry Coetsee, Marla Catherine Ligand-induced selective signalling at the gonadotrophin releasing hormone receptor |
| thesis_degree_str | Doctoral |
| title | Ligand-induced selective signalling at the gonadotrophin releasing hormone receptor |
| title_full | Ligand-induced selective signalling at the gonadotrophin releasing hormone receptor |
| title_fullStr | Ligand-induced selective signalling at the gonadotrophin releasing hormone receptor |
| title_full_unstemmed | Ligand-induced selective signalling at the gonadotrophin releasing hormone receptor |
| title_short | Ligand-induced selective signalling at the gonadotrophin releasing hormone receptor |
| title_sort | ligand induced selective signalling at the gonadotrophin releasing hormone receptor |
| topic | Medical Biochemistry |
| url | http://hdl.handle.net/11427/3123 |
| work_keys_str_mv | AT coetseemarlacatherine ligandinducedselectivesignallingatthegonadotrophinreleasinghormonereceptor |