A5041530320- HER2/EGFR in Cancer Research
- Monoclonal and Polyclonal Antibodies Research
- Advanced Fluorescence Microscopy Techniques
- Lung Cancer Treatments and Mutations
- Glycosylation and Glycoproteins Research
- Advanced Biosensing Techniques and Applications
- Cell Image Analysis Techniques
- Computational Drug Discovery Methods
- PI3K/AKT/mTOR signaling in cancer
- Advanced Electron Microscopy Techniques and Applications
- Microbial Natural Products and Biosynthesis
- Cellular Mechanics and Interactions
- Angiogenesis and VEGF in Cancer
- Cellular transport and secretion
- Optical Coherence Tomography Applications
- Genetics, Bioinformatics, and Biomedical Research
- Graphene and Nanomaterials Applications
- Cancer Treatment and Pharmacology
- Laser-Ablation Synthesis of Nanoparticles
- Advanced Thermodynamics and Statistical Mechanics
- Advanced biosensing and bioanalysis techniques
- Ubiquitin and proteasome pathways
- CAR-T cell therapy research
- Machine Learning in Bioinformatics
- Hippo pathway signaling and YAP/TAZ
Science and Technology Facilities Council
2011-2024
Rutherford Appleton Laboratory
2011-2024
Research Complex at Harwell
2011-2020
Daresbury Laboratory
2006-2009
Abstract Epidermal growth factor receptor (EGFR) signalling is activated by ligand-induced dimerization. Notably, ligand binding also induces EGFR oligomerization, but the structures and functions of oligomers are poorly understood. Here, we use fluorophore localization imaging with photobleaching to probe structure oligomers. We find that at physiological epidermal (EGF) concentrations, assembles into oligomers, as indicated pairwise distances receptor-bound fluorophore-conjugated EGF...
Abstract The Epidermal Growth Factor Receptor (EGFR) is frequently found to be mutated in non-small cell lung cancer. Oncogenic EGFR has been successfully targeted by tyrosine kinase inhibitors, but acquired drug resistance eventually overcomes the efficacy of these treatments. Attempts surmount this therapeutic challenge are hindered a poor understanding how and why cancer mutations specifically amplify ligand-independent auto-phosphorylation signals enhance survival amplification related...
Abstract Our current understanding of epidermal growth factor receptor (EGFR) autoinhibition is based on X-ray structural data monomer and dimer fragments does not explain how mutations achieve ligand-independent phosphorylation. Using a repertoire imaging technologies simulations we reveal an extracellular head-to-head interaction through which ligand-free polymer chains various lengths assemble. The architecture the prevents kinase-mediated dimerisation. latter, afforded by mutation or...
While targeted therapy against HER2 is an effective first-line treatment in HER2+ breast cancer, acquired resistance remains a clinical challenge. The pseudokinase HER3, heterodimerisation partner of HER2, widely implicated the to HER2-mediated therapy. Here, we show that lapatinib, ATP-competitive inhibitor able induce proliferation cooperatively with HER3 ligand neuregulin. This counterintuitive synergy between and growth factor depends on their ability promote atypical HER2-HER3...
Fluorescence fluctuation super-resolution microscopy (FF-SRM) has emerged as a promising method for the fast, low-cost, and uncomplicated imaging of biological specimens beyond diffraction limit. Among FF-SRM techniques, radial (SRRF) is popular technique but prone to artifacts, resulting in low fidelity, especially under conditions high-density fluorophores. In this Letter, we developed novel, best our knowledge, combinatory computational method, namely VeSRRF, that demonstrated superior...
The ability of epidermal growth factor receptor (EGFR) to control cell fate is defined by its affinity for ligand. Current models suggest that ligand-binding heterogeneity arises from negative cooperativity in signaling dimers, which the asymmetry extracellular region Drosophila EGFR has recently provided a structural basis. However, no apparent isolated human EGFR. Human also differs found only full-length receptors cells. To gain insights into situ, we developed an approach based on...
We have developed a wide-field total-internal-reflection fluorescence microscope capable of imaging single molecules in live cells, resolved both wavelength and polarization. show resonance energy transfer between pairs fluorescent bound to signaling receptors the plasma membrane cells demonstrate importance polarization discrimination addition separation.
Carbon based materials are attractive for biological applications because of their excellent biocompatibility profile. Porous carbons with high specific surface area particularly interesting it is possible in principle to leverage properties deliver drug payloads. In this work, porous carbon microspheres were prepared and studied solution cells. Raman optical tweezer trapping microspheres, excited at 532 nm, results graphitization incandescence solvents that display poor heat conduction....
The elaboration of polarity is central to organismal development and the maintenance functional epithelia. Among controls determining are PAR proteins, PAR6, aPKCι PAR3, regulating both known unknown effectors. Here, we identify FARP2 as a 'RIPR' motif-dependent partner substrate that required for efficient polarisation junction formation. Binding conferred by FERM/FA domain-kinase domain interaction detachment promoted aPKCι-dependent phosphorylation. shown promote GTP loading Cdc42, which...
The Human Epidermal Growth Factor Receptor (HER) family of receptor tyrosine kinases consists four, single pass, transmembrane homologs (HER1-4) that act to regulate many critical processes in normal and tumor cells. HER2 is overexpressed tumors, the deregulated proliferation cancerous cells driven by cooperation with its preferred partner, HER3. assessment in-situ organization tagged HER3 using super-resolution microscopy reveals quantitative Single Molecule Localization Microscopy (SMLM)...
Despite being catalytically defective, pseudokinases are typically essential players of cellular signalling, acting as allosteric regulators their active counterparts. Deregulation a growing number has been linked to human diseases, making therapeutic targets interest. Pseudokinases can be dynamic, adopting specific conformations critical for function. Interfering with role, small molecules that would lock in conformation preventing productive partner interactions, is an attractive strategy...
We combine single molecule fluorescence orientation imaging with single-pair resonance energy transfer microscopy, using a total internal reflection microscope. show how angles and FRET efficiencies can be determined for membrane proteins at the level provide data from epidermal growth factor receptor system in cells.
Optics clustered to output unique solutions (OCTOPUS) is a microscopy platform that combines single molecule and ensemble imaging methodologies. A novel aspect of OCTOPUS its laser excitation system, which consists central core interlocked continuous wave pulsed sources, launched into optical fibres linked via combiners. Fibres are plugged wall-mounted patch panels reach end-stations in adjacent rooms. This allows multiple tailor-made combinations colours time characteristics be shared by...
The crystallographic structures of functional fragments ErbBs have provided excellent insights into the geometry growth factor binding and receptor dimerization. By placing together to build structural models entire receptors, we expect understand how these enzymes are allosterically regulated; however, several predictions from inconsistent with experimental evidence cells. opening this gap underlines need investigate intact by combining cellular studies a full picture.