31 research outputs found
Structure and Dynamics of the EGF Receptor as Revealed by Experiments and Simulations and Its Relevance to Non-Small Cell Lung Cancer
The epidermal growth factor receptor (EGFR) is historically the prototypical receptor
tyrosine kinase, being the first cloned and the first where the importance of ligand-induced dimer
activation was ascertained. However, many years of structure determination has shown that EGFR is
not completely understood. One challenge is that the many structure fragments stored at the PDB only
provide a partial view because full-length proteins are flexible entities and dynamics play a key role in
their functionality. Another challenge is the shortage of high-resolution data on functionally important
higher-order complexes. Still, the interest in the structure/function relationships of EGFR remains
unabated because of the crucial role played by oncogenic EGFR mutants in driving non-small cell
lung cancer (NSCLC). Despite targeted therapies against EGFR setting a milestone in the treatment
of this disease, ubiquitous drug resistance inevitably emerges after one year or so of treatment.
The magnitude of the challenge has inspired novel strategies. Among these, the combination of
multi-disciplinary experiments and molecular dynamic (MD) simulations have been pivotal in
revealing the basic nature of EGFR monomers, dimers and multimers, and the structure-function
relationships that underpin the mechanisms by which EGFR dysregulation contributes to the onset of
NSCLC and resistance to treatment
The architecture of EGFR's basal complexes reveals autoinhibition mechanisms in dimers and oligomers
Our current understanding of epidermal growth factor receptor (EGFR) autoinhibition is based on X-ray structural data of monomer and dimer receptor fragments and does not explain how mutations achieve ligand-independent phosphorylation. Using a repertoire of imaging technologies and simulations we reveal an extracellular head-to-head interaction through which ligand-free receptor polymer chains of various lengths assemble. The architecture of the head-to-head interaction prevents kinase-mediated dimerisation. The latter, afforded by mutation or intracellular treatments, splits the autoinhibited head-to-head polymers to form stalk-to-stalk flexible non-extended dimers structurally coupled across the plasma membrane to active asymmetric tyrosine kinase dimers, and extended dimers coupled to inactive symmetric kinase dimers. Contrary to the previously proposed main autoinhibitory function of the inactive symmetric kinase dimer, our data suggest that only dysregulated species bear populations of symmetric and asymmetric kinase dimers that coexist in equilibrium at the plasma membrane under the modulation of the C-terminal domain
Mechanisms of action of EGFR tyrosine kinase receptor incorporated in extracellular vesicles
EGFR and some of the cognate ligands extensively traffic in extracellular vesicles (EVs) from different biogenesis pathways. EGFR belongs to a family of four homologous tyrosine kinase receptors (TKRs). This family are one of the major drivers of cancer and is involved in several of the most frequent malignancies such as non-small cell lung cancer, breast cancer, colorectal cancer and ovarian cancer. The carrier EVs exert crucial biological effects on recipient cells, impacting immunity, pre-metastatic niche preparation, angiogenesis, cancer cell stemness and horizontal oncogene transfer. While EV-mediated EGFR signalling is important to EGFR-driven cancers, little is known about the precise mechanisms by which TKRs incorporated in EVs play their biological role, their stoichiometry and associations to other proteins relevant to cancer pathology and EV biogenesis, and their means of incorporation in the target cell. In addition, it remains unclear whether different subtypes of EVs incorporate different complexes of TKRs with specific functions. A raft of high spatial and temporal resolution methods is emerging that could solve these and other questions regarding the activity of EGFR and its ligands in EVs. More importantly, methods are emerging to block or mitigate EV activity to suppress cancer progression and drug resistance. By highlighting key findings and areas that remain obscure at the intersection of EGFR signalling and EV action, we hope to cross-fertilise the two fields and speed up the application of novel techniques and paradigms to both
Mechanisms of Action of EGFR Tyrosine Kinase Receptor Incorporated in Extracellular Vesicles
Cooperation and Interplay between EGFR Signalling and Extracellular Vesicle Biogenesis in Cancer
Structure and Dynamics of the EGF Receptor as Revealed by Experiments and Simulations and Its Relevance to Non-Small Cell Lung Cancer
A systematic investigation of differential effects of cell culture substrates on the extent of artifacts in single-molecule tracking
Cooperation and interplay between EGFR signalling and extracellular vesicle biogenesis in cancer
Epidermal growth factor receptor (EGFR) takes centre stage in carcinogenesis throughout its entire cellular trafficking odyssey. When loaded in extracellular vesicles (EVs), EGFR is one of the key proteins involved in the transfer of information between parental cancer and bystander cells in the tumour microenvironment. To hijack EVs, EGFR needs to play multiple signalling roles in the life cycle of EVs. The receptor is involved in the biogenesis of specific EV subpopulations, it signals as an active cargo, and it can influence the uptake of EVs by recipient cells. EGFR regulates its own inclusion in EVs through feedback loops during disease progression and in response to challenges such as hypoxia, epithelial-to-mesenchymal transition and drugs. Here, we highlight how the spatiotemporal rules that regulate EGFR intracellular function intersect with and influence different EV biogenesis pathways and discuss key regulatory features and interactions of this interplay. We also elaborate on outstanding questions relating to EGFR-driven EV biogenesis and available methods to explore them. This mechanistic understanding will be key to unravelling the functional consequences of direct anti-EGFR targeted and indirect EGFR-impacting cancer therapies on the secretion of pro-tumoural EVs and on their effects on drug resistance and microenvironment subversion