Proposed mechanism of EGFR feedback monomerization upon EGF stimulation.

After EGF challenging, two EGFR monomers associate on the plasma membrane to form an asymmetric dimer. The asymmetric dimer formation activates the kinase domain which transphosphorylates tyrosine residues at the C-termini of the receptor, three of which (pY1173, pY1148, pY992) recruit PLCγ1. EGFR phosphorylates PLCγ1 on Y783 for activation. PLCγ1 hydrolyses PIP₂ forming DAG. DAG activates nPKCs, which phosphorylates PKD at S744 and S748 for activation. PKD causes EGFR phosphorylation at T654 and/or T669 to shift the monomer-dimer equilibrium of liganded EGFR back towards the monomer. The insets show the close-up of the JM part. The two PDB files (2M20, 3GOP) were superimposed and aligned in the JM-A region to obtain presented images.