EGFR-Activ · Epidermal growth factor receptor (EGFR) activation by cytohesins - Structural Insights
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2015-05-04 → 2017-05-03
- EU contribution
- €159,461
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
Epidermal growth factor receptor (EGFR) activation by cytohesins - Structural Insights
In humans, EGFR’s incorrect signalling is associated with neurodegenerative diseases and a number of cancers. Thus, mechanisms that modulate the activation of these receptors are high profile drug targets. However, many of the drugs in use cause a variety of skin toxicities and some types of cancer seem to be resistant. Furthermore, achieving the high level of structural information required for the study of these systems is a complex task. Therefore, new approaches to study and fight EGF receptor-dependent malignancies are urgently needed. The overall objectives of the projects focused on a better understanding of cytoplasmic components that may play a, yet not well characterized, role in EGFR activation. Better insights into these factors may help to develop new therapeutic strategies to target various EGFR-related pathogenic signalling pathways. To obtain reliable information of these molecular details, it is of fundamental importance to also apply high-resolution approaches that on the one hand provide structural information in a site-resolved manner and on the other hand are applicable to environmental conditions that sufficiently mimic native conditions. For this reason, mainly high-resolution solution-state NMR was used at temperature, buffer and environmental conditions such as detergent free membrane mimetics at physiological pH and temperature. The structural NMR studies in particular focused on the role of its juxtamembrane domain (JM), the membrane environment and cytoplasmic co-factors (i.e. the Sec7 of cytohesin-2). Overall, we succeeded in identifying interactions and characterizing structural details of the JM-Sec7 binding as well as JM-membrane association. For the latter, we also identified a dependence of the lipid composition of the membrane mimetic. The obtained data may be transferred towards academic and non-academic environments and contribute to the global knowledge of EGFR-signalling and to the discovery of novel therapeutic agents with the potential to save human lives.
Data: CORDIS, © European Union
Project objective
The epidermal growth factor receptor (EGFR) is a key player in many biological responses and its aberrant function is associated with numerous diseases, including a number of cancers. Despite the significant benefits of anti-EGFR agents in some tumours, many challenges remain in the improvement of EGFR-targeted therapies.This proposal targets cofactors in the EGFR signalling that, so far, were not exploited therapeutically and hence may not only contribute to the global effort in the understanding of this system but may also open new doors to the development of new therapeutic agents. The aim is to use Nuclear Magnetic Resonance (NMR) to obtain structural insights into EGFR activation covering three main aspects: i) modulation of activity by the transmembrane and juxtamembrane domains, ii) the role of the cell membrane and iii) the role of cytohesins in EGFR activation. For this, selected protein constructs will be prepared and their structure and interactions will be characterized. In parallel, new NMR methodology to improve the study of challenging biological samples, specifically EGFR, will be developed. The work plan will provide an innovative and multidisciplinary training covering different areas in Life Sciences and allow the researcher to experience work in an industrial environment through a secondment. We anticipate to obtain structural information that contributes to the global knowledge on these systems and to the discovery novel therapeutic agents. Moreover, the innovative methodologies that will be used in terms of the acquisition of multidimensional NMR experiments have the potential to change the way current investigation of challenging biological samples is done by NMR spectroscopy.
Original text from CORDIS.
Participants
- HEINRICH-HEINE-UNIVERSITAET DUESSELDORF · DusseldorfCoordinatorGermany
Links
Data: CORDIS, © European Union