The role of the Integrin β3 Adhesome in Angiogenesis

Atkinson, Samuel (2018) The role of the Integrin β3 Adhesome in Angiogenesis. Doctoral thesis, University of East Anglia.

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                Abstract

                Angiogenesis, the formation of new blood vessels from those that already exist, plays an essential role in development, homeostasis and tumour growth. As such, targeting angiogenesis is seen as crucial in treatment of cardiovascular diseases or cancer. Therapies directed against vascular endothelial growth factor and its major receptor, VEGFR2 (vascular endothelial growth factor receptor 2), whilst effective in a number of cancers, are not without side-effects due to the role this signalling pathway plays in vascular homeostasis. Because of their restricted expression, fibronectin binding endothelial integrins, especially αvβ3- and α5β1-integrins, have emerged as alternative anti-angiogenic targets to neovasculature, particularly in the case of β3. However, neither global nor conditional knockouts of these integrins block tumour angiogenesis beyond acute deletions, and clinical trials of blocking antibodies and peptides directed against these extracellular matrix receptors have been disappointing. To gain novel insight into how αvβ3-integrin regulates outside-in signal transmission, in this thesis we have optimised an enrichment and mass spectrometry workflow to undertake an unbiased analysis of the molecular composition of the mature endothelial adhesome, and profiled changes that occur when β3-integrin function or expression are manipulated. In so doing, we have uncovered β3-integrin dependent changes in microtubule behaviour that affect cell migration and offered some potential explanations as to why current inhibitors have failed clinical trials. β3 negatively regulates microtubule stability/targeting to focal adhesions and these changes are driven by Rcc2 (Regulator of Chromatin Condensation 2) and Anxa2 (Annexin A2) regulation of Rac1 (Ras-related C3 botulinum toxin substrate 1). As a result, cell migration, angiogenesis and tumour growth in the absence of β3 are susceptible to low doses of clinically relevant microtubule inhibitors.

                Item Type: Thesis (Doctoral)
                Faculty \ School: Faculty of Science > School of Biological Sciences
                Depositing User: Gillian Aldus
                Date Deposited: 14 Sep 2018 12:08
                Last Modified: 14 Sep 2018 12:08
                URI: https://ueaeprints.uea.ac.uk/id/eprint/68286
                DOI:

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