Ligand-induced EGF receptor oligomerization is kinase-dependent and enhances internalization |
| |
Authors: | Hofman Erik G Bader Arjen N Voortman Jarno van den Heuvel Dave J Sigismund Sara Verkleij Arie J Gerritsen Hans C van Bergen en Henegouwen Paul M P |
| |
Institution: | Department of Cellular Dynamics, Science Faculty, Utrecht University, 3584 CH Utrecht, The Netherlands. |
| |
Abstract: | The current activation model of the EGF receptor (EGFR) predicts that binding of EGF results in dimerization and oligomerization of the EGFR, leading to the allosteric activation of the intracellular tyrosine kinase. Little is known about the regulatory mechanism of receptor oligomerization. In this study, we have employed FRET between identical fluorophores (homo-FRET) to monitor the dimerization and oligomerization state of the EGFR before and after receptor activation. Our data show that, in the absence of ligand, ~40% of the EGFR molecules were present as inactive dimers or predimers. The monomer/predimer ratio was not affected by deletion of the intracellular domain. Ligand binding induced the formation of receptor oligomers, which were found in both the plasma membrane and intracellular structures. Ligand-induced oligomerization required tyrosine kinase activity and nine different tyrosine kinase substrate residues. This indicates that the binding of signaling molecules to activated EGFRs results in EGFR oligomerization. Induction of EGFR predimers or pre-oligomers using the EGFR fused to the FK506-binding protein did not affect signaling but was found to enhance EGF-induced receptor internalization. Our data show that EGFR oligomerization is the result of EGFR signaling and enhances EGFR internalization. |
| |
Keywords: | Fluorescence Resonance Energy Transfer (FRET) Protein Assembly Protein Phosphorylation Receptor Endocytosis Signal Transduction EGF EGF Receptor |
本文献已被 PubMed 等数据库收录! |
|