Recent findings showed that preformed fibrils (PFFs) of misfolded proteins, including α-synuclein (α-syn) and amyloid-β (Aβ), activate EGFR in cell cultures and animal models of amyloid propagation. Comparing these supramolecular structures to normal EGFR ligands such as EGF and HB-EGF suggests that these PFFs might trigger the formation of high order clustering of EGFR that stimulates the aggregation of EGFR tyrosine kinase domain (EGFR-TKD) which is known to form fibrils. Subsequently, self-assembled fibril of EGFR-TKDs itself can serve as a seed to induce aggregation of monomeric forms of misfolded proteins in cytoplasm or endosomes. In this model, EGFR serves as an amyloidogenic receptor to facilitate (1) cellular uptake of exogenous PFFs and (2) seeding of endogenous misfolded proteins.