Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/113111
Type: Theses
Title: Role of insulin receptor isoform A in breast cancer
Author: Li, Liang
Issue Date: 2017
School/Discipline: School of Biological Sciences
Abstract: Insulin like growth factor II (IGF-II) binds to Insulin Receptor isoform A (IR-A) to sustain cell growth and proliferation. This autocrine loop exists in many human carcinomas and provides an additional proliferation and survival pathway to the type 1 insulin-like growth factor (IGF-1R) signalling pathway. In addition, activation of the IGF-II/IR-A autocrine loop provides a mechanism of resistance drugs target the type 1 insulin-like growth factor (IGF- 1R). However, the mechanism of how IGF-II/IR-A differentiates itself from the IGF-II/IGF- 1R pathway is still unclear. Additionally, a novel phosphorylation site Thr¹¹⁴⁸ (numbered in IR-A) of IR was found in response to insulin stimulation and its phosphorylation in the absence of any Tyr¹¹⁴⁶, Tyr¹¹⁵⁰, and Tyr¹¹⁵¹ phosphorylation. We thus hypothesis that the The phosphorylation of Thr¹¹⁴⁸ inhibits the phosphorylation of Tyr¹¹⁴⁶, Tyr¹¹⁵⁰, and Tyr¹¹⁵¹ of the activation loop, which is possibly due to steric hindrance and electrostatic repulsion of the phosphate group on Thr¹¹⁴⁸ preventing interaction of the activation loop with the tyrosine kinase. The key areas of investigation included: 1. Investigate the role of Thr¹¹⁴⁸ phosphorylation in IR-A by overexpress the wild-type IR-A and its mutants Thr¹¹⁴⁸Ala and Thr¹¹⁴⁸Asp in R⁻ (Mouse fibroblast cells with IGF- 1R KO). 2. Knock down the IR and IGF-1R separately in MDA-MB-231 and MCF-7 cells using inducible expressed miR30 shRNA and measure their characteristics (proliferation, migration, epithelial–mesenchymal transition) in response to insulin, IGF-I, and IGFII stimulation separately. 3. Quantitative phosphoproteomics was conducted to compare the insulin/IR-A and IGFII/ IR-A signalling pathway with MDA MB 231 IGF-1RKD cell. The key findings from this work included: included: 1. Thr¹¹⁴⁸Ala and Thr¹¹⁴⁸Asp inhibit the insulin sensitivity of IR-A, which indicate the Thr¹¹⁴⁸ phosphorylation inhibits the IR activation. 2. IRKD has no effect on proliferation of MCF-7 cells and the migration of MDA-MB- 231 cells, but increases the proliferation of MDA-MB-231 cells. 3. IGF-1RKD inhibits the proliferation of both MCF-7 cells and MDA-MB-231 cells, but increases the migration of MDA-MB-231 cells. 4. IGF-1R increases the insulin sensitivity of MDA-MB-231 cells, shown by the Akt activation. 5. Insulin and IGF-II are confirmed to induce different signalling pathways confirmed by quantitative phosphoproteomics study. IGF-II is preferentially regulates the migration and stemness of MDA-MB-231 IGF-1RKD cells. Many markers are identified but verifications are still needed. Drug developed on the verified markers can be used to treat the patients who are resistant to anti-IGF-1R inhibitor.
Advisor: Forbes, Briony Evelyn
Hoffmann, Peter
Dissertation Note: Thesis (Ph.D.) -- University of Adelaide, School of Biological Sciences, 2018
Keywords: Insulin receptor
cancer
IGF-II
Provenance: This electronic version is made publicly available by the University of Adelaide in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. This thesis may incorporate third party material which has been used by the author pursuant to Fair Dealing exceptions. If you are the owner of any included third party copyright material you wish to be removed from this electronic version, please complete the take down form located at http://www.adelaide.edu.au/legals
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