Abstract
Crystallographic studies have offered understanding of how receptor tyrosine kinases from the ErbB family are regulated by their growth factor ligands. A conformational change of the EGFR (ErbB1) was shown to occur upon ligand binding, where a solely ligand-mediated mode of dimerization/activation was documented. However, this dogma of dimerization/activation was revolutionized by the discovery of constitutively active ligand-independent EGFR mutants. In addition, other ligand-independent activation mechanisms may occur. We have shown that oxidative stress (ox-stress), induced by hydrogen peroxide or cigarette smoke, activates EGFR differently than its ligand, EGF, thereby inducing aberrant phosphorylation and impaired trafficking and degradation of EGFR. Here we demonstrate that ox-stress activation of EGFR is ligand-independent, does not induce “classical” receptor dimerization and is not inhibited by the tyrosine kinase inhibitor AG1478. Thus, an unprecedented, apparently activated, state is found for EGFR under ox-stress. Furthermore, this activation mechanism is temperature-dependent, suggesting the simultaneous involvement of membrane structure. We propose that ceramide increase under ox-stress disrupts cholesterol-enriched rafts leading to EGFR re-localization into the rigid, ceramide-enriched rafts. This increase in ceramide also supports EGFR aberrant trafficking to a peri-nuclear region. Therefore, the EGFR unprecedented and activated conformation could be sustained by simultaneous alterations in membrane structure under ox-stress.
Highlights
The epidermal growth factor receptor (EGFR, ErbB1) is a member of the ErbB family of receptor tyrosine kinases, which includes ErbB2, ErbB3, and ErbB4
Cells were exposed to either 100 ng/ml EGF for 15 min. or 1 unit (U)/ml glucose oxidase (GO; to generate H2O2) for 30 min. in the absence or presence of the monoclonal antibody (mAb)
Phosphorylation of the EGFR by EGF was blocked by the mAb whereas phosphorylation by GO could not be inhibited (Fig. 1)
Summary
The epidermal growth factor receptor (EGFR, ErbB1) is a member of the ErbB family of receptor tyrosine kinases, which includes ErbB2, ErbB3, and ErbB4. Recent advancements in crystallographic studies have demonstrated that EGFR dimerization occurs upon the binding of one EGF molecule to one EGFR, which releases the extracellular portion of the receptor from its ‘‘tethered’’ conformation. This exposes the otherwise buried ‘‘dimerization arm’’, which can interact with its dimerization partner in an entirely receptor-mediated back-to-back orientation [8,9,10,11]
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