Cryo-EM structure of the extracellular module of the full-length EGFR bound to EGF "tips-juxtaposed" conformation

Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses ^[1–13]. Known ligands include EGF, TGFA/TGF-alpha, AREG, epigen/EPGN, BTC/betacellulin, epiregulin/EREG and HBEGF/heparin-binding EGF ^{[14, 15, 16, 17, 10, 11, 18, 19, 20]}. Ligand binding triggers receptor homo- and/or heterodimerization and autophosphorylation on key cytoplasmic residues ^{[21, 22, 23, 8, 24]}.

The phosphorylated receptor recruits adapter proteins like GRB2 which in turn activates complex downstream signaling cascades ^{[21, 22, 23, 8, 24]}. Activates at least 4 major downstream signaling cascades including the RAS-RAF-MEK-ERK, PI3 kinase-AKT, PLCgamma-PKC and STATs modules ^[10]. May also activate the NF-kappa-B signaling cascade ^[25].

Also directly phosphorylates other proteins like RGS16, activating its GTPase activity and probably coupling the EGF receptor signaling to the G protein-coupled receptor signaling ^[26]. Also phosphorylates MUC1 and increases its interaction with SRC and CTNNB1/beta-catenin ^[27]. Positively regulates cell migration via interaction with CCDC88A/GIV which retains EGFR at the cell membrane following ligand stimulation, promoting EGFR signaling which triggers cell migration ^[28].

Acts as a positive regulator of cGAS-STING signaling by mediating tyrosine phosphorylation of STING1, promoting production of type I interferon (IFN-alpha and IFN-beta), while inhibiting STING1 ability to regulate autophagy ^[29]. Plays a role in enhancing learning and memory performance (By similarity). Plays a role in mammalian pain signaling (long-lasting hypersensitivity) (By similarity) May act as an antagonist of EGF action (Microbial infection) Acts as a receptor for hepatitis C virus (HCV) in hepatocytes and facilitates its cell entry.

Mediates HCV entry by promoting the formation of the CD81-CLDN1 receptor complexes that are essential for HCV entry and by enhancing membrane fusion of cells expressing HCV envelope glycoproteins