The role of the integrin β3 adhesome in angiogenesis

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