Inhibition of Receptor Dimerization as a Novel Negative Feedback Mechanism of EGFR Signaling
Malgorzata Kluba
Yves Engelborghs
Johan Hofkens
Hideaki Mizuno
10.1371/journal.pone.0139971
https://plos.figshare.com/articles/dataset/_Inhibition_of_Receptor_Dimerization_as_a_Novel_Negative_Feedback_Mechanism_of_EGFR_Signaling_/1575199
<div><p>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 Ca<sup>2+</sup> 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.</p></div>
2015-10-14 04:12:03
EGFR dimer formation
receptor monomerization
monomeric state
feedback loop
pkd
epidermal growth factor receptor
protein kinase D
EGFR Signaling Dimerization
feedback mechanism
juxtamembrane threonine residues
raster image correlation spectroscopy
Signal transduction
dimerization state
oscillatory behavior
Receptor Dimerization
2.5 min