title: Inhibition of Receptor Dimerization as a Novel Negative Feedback Mechanism of EGFR Signaling.
abstract: Dimerization of the epidermal growth factor receptor (EGFR) is crucial for initiating signal transduction. We employed raster image correlation spectroscopy to continuously monitor the EGFR monomer-dimer equilibrium in living cells. EGFR dimer formation upon addition of EGF showed oscillatory behavior with a periodicity of about 2.5 min, suggesting the presence of a negative feedback loop to monomerize the receptor. We demonstrated that monomerization of EGFR relies on phospholipase Cγ, protein kinase C, and protein kinase D (PKD), while being independent of Ca2+ signaling and endocytosis. Phosphorylation of the juxtamembrane threonine residues of EGFR (T654/T669) by PKD was identified as the factor that shifts the monomer-dimer equilibrium of ligand bound EGFR towards the monomeric state. The dimerization state of the receptor correlated with the activity of an extracellular signal-regulated kinase, downstream of the EGFR. Based on these observations, we propose a novel, negative feedback mechanism that regulates EGFR signaling via receptor monomerization.
authors.affiliation: Laboratory of Biomolecular Network Dynamics, Biochemistry, Molecular and Structural Biology Section, Department of Chemistry, KU Leuven, Celestijnenlaan 200G box 2403, 3001, Heverlee, Belgium.
authors.forename: Malgorzata
authors.initials: M
authors.lastname: Kluba
authors.affiliation: Laboratory of Biomolecular Network Dynamics, Biochemistry, Molecular and Structural Biology Section, Department of Chemistry, KU Leuven, Celestijnenlaan 200G box 2403, 3001, Heverlee, Belgium.
authors.forename: Yves
authors.initials: Y
authors.lastname: Engelborghs
authors.affiliation: Molecular Imaging and Photonics, Department of Chemistry, KU Leuven, Celestijnenlaan 200F, 3001, Heverlee, Belgium.
authors.forename: Johan
authors.initials: J
authors.lastname: Hofkens
authors.affiliation: Laboratory of Biomolecular Network Dynamics, Biochemistry, Molecular and Structural Biology Section, Department of Chemistry, KU Leuven, Celestijnenlaan 200G box 2403, 3001, Heverlee, Belgium.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Mizuno
mesh_terms: D000818:Animals; D016466:CHO Cells; D020013:Calcium Signaling / Q000235:genetics; D002462:Cell Membrane / Q000378:metabolism*; D003412:Cricetulus; D019281:Dimerization; D004705:Endocytosis / Q000235:genetics; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D010766:Phosphorylation; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D008024:Ligands; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases