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In vivo inhibition of epidermal growth factor receptor autophosphorylation prevents receptor internalization |
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| Authors: | Michael Wolff Kay Tetzlaff Michael C Nivens Franz-Josef Schneider Birgit Jung Jens Hohlfeld Ralf Heilker |
| Institution: | aDept. of Lead Discovery, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str.65, D-88397 Biberach, Germany;bDept. of Clinical Operations Respiratory, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, CT 06877, USA;cDept. of Pulmonary Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str.65, D-88397 Biberach, Germany;dFraunhofer Institute Toxicology and Experimental Medicine (ITEM), Nikolai-Fuchs-Straße 1, D-30625 Hannover, Germany |
| Abstract: | The question whether epidermal growth factor (EGF)-induced receptor endocytosis requires the prior autophosphorylation via the EGF receptor (EGFR) kinase domain has been a matter of long-standing debate. In the airway epithelial cell line NCI-H292, the EGFR kinase domain inhibitor BIBW 2948 BS was found to inhibit both autophosphorylation and subsequent internalization of the endogenous EGFR with similar IC50 values. Applying an ex vivo EGFR internalization assay in a clinical study, the in vivo effect of inhalatively administered BIBW 2948 BS was determined directly at the targeted receptor in airway tissues from COPD patients. In these experiments, the in vivo inhibition of the EGFR kinase domain prevented the EGF-induced internalization of EGFR. |
| Keywords: | Autophosphorylation Epidermal growth factor receptor Fluorescence microscopy Image analysis Internalization |
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