Mechanism of transmembrane signalling by EGFR

ongoing

According to the latest estimates from the European Cancer Information System, the incidence and mortality from cancer is projected to increase in the next 20 years. Therefore, there is a strong urge to design safe and effective therapeutic approaches to manage cancer progression and ease the burden of the disease. Although the etiology of cancer is highly complex and multifactorial, disruption of the Epidermal Growth Factor Receptor (EGFR) function is commonly associated with the development of several types of cancers. Despite being in the spotlight since its discovery in the late 70’s, several important aspects of EGFR function (e.g oligomerization and receptor bias) still remain largely unexplored. Inspired by this gap of knowledge, the main aim of this proposal is to shed light into the molecular mechanisms governing EGFR oligomerization and signaling. EGFR in dimeric and oligomeric assemblies will be resolved by Cryo-Electron Tomography (Cryo-ET) in near-native conditions. As substantial differences in the transmission of response between dimer and oligomeric EGFR states can arise (receptor bias), these aspects will also be extensively validated/analyzed in vitro. Cryo-ET is revolutionizing the field of structural biology, as proteins can now be resolved without laborious purification protocols which potentially alter structure and function of target proteins. Although promising, this technique is still at early stages of development and only large proteins have been successfully resolved. By resolving the structure of a relatively small and flexible protein, the boundaries of this technique would be expanded and be more applicable for the structural characterization of transmembrane receptors. From the biological point of view, knowing the conditions in which EGFR assemblies are formed and that these assemblies have distinct signal properties, specific therapeutic approaches can be designed to treat cancer minimising the occurrence of side effects.