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- W2001924260 abstract "Deregulation of the epidermal growth factor receptor (EGFR) signalling has been correlated with the development of a variety of human carcinomas. Receptor dimerization and phosphorylation are amongst the earliest events in signal transduction. Binding of EGF is thought to induce a conformational change which unfolds an ectodomain loop required for dimerization. It may also induce important allosteric changes in the cytoplasmic domain. Despite these findings, ensemble-averaging methods could not resolve the details of receptor activation in situ. Here, we used two-color single-molecule imaging to study the effect of ATP-competitive small molecule tyrosine kinase inhibitors (TKI) and phosphatase-based manipulation of EGFR phosphorylation on live cells. Ligand bound receptors were tracked on the plasma membrane with a sophisticated Bayesian segmentation tracking algorithm and the distribution of dimer lifetimes was fitted to a single-exponential to extract dimer off-rates (koff). Our data show that, pre-treatment with type I TKI, gefitinib (active conformation binder) stabilizes the EGFR homodimer. Over-expression of EGFR specific DEP-1 phosphatase was also found to have a stabilizing effect on the homodimer. When a nonactivating anti-EGFR antibody, Snap-425 single-chain variable fragment that competes for EGF binding was used as a ligand, no significant difference in the koff of the dimer could be detected. Conformational changes of the cytoplasmic part of the receptor upon gefitinib pre-treatment were also confirmed by changes in Fluorescence Resonance Energy Transfer (FRET) efficiency detected by ensemble FRET/FLIM (Fluorescence Lifetime Intensity Microscopy). These results provide direct evidence that receptor phosphorylation is linked to dimer stability. The phosphorylated and non-phosphorylated receptors exhibit different kinetics and cytoplasmic conformations which may account for the heterogeneity in ligand-binding affinity observed through a concave-up Scatchard plot." @default.
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- W2001924260 date "2014-01-01" @default.
- W2001924260 modified "2023-09-28" @default.
- W2001924260 title "Modulation of EGFR Dimer Stability by Manipulation of Phosphorilation in Situ" @default.
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- W2001924260 doi "https://doi.org/10.1016/j.bpj.2013.11.628" @default.
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