Docking Analysis of Drugs Used in the Treatment of Alzheimer's Disease, Using Cell Membrane Receptors and Enzymes of the Kynurenine Pathway: A Pilot Study.

The epidermal growth factor receptor (EGFR, also known as ErbB1/HER1) is a transmembrane receptor tyrosine kinase of the ErbB family that regulates cell proliferation, survival, migration, and differentiation (; ). EGFR is activated by several ligands, including epidermal growth factor (EGF), transforming growth factor- (TGF-α), heparin-binding EGF-like growth factor (HB-EGF), betacellulin (BTC), amphiregulin (AREG), epiregulin (EREG), and epigen (EPGN), which are released from membrane-bound precursors mainly through ADAM10/17-mediated proteolytic cleavage (; ; ), (). Ligand binding induces EGFR homo- or heterodimerization with other ErbB receptors, activating downstream signaling pathways including RAS/RAF/MEK/ERK–MAPK, PI3K/AKT/mTOR, PLCγ/PKC, SRC, JNK, and JAK/STAT cascades, which collectively regulate diverse cellular functions in the nervous system (, ; ). These pathways are involved in neuronal repair and in the pathobiology of several neurodegenerative diseases, as summarized in , , respectively. The biological outcome of EGFR activation is determined by multiple factors, including ligand availability, signal intensity and duration, receptor dimerization partners, and the responding cell type. Consequently, EGFR signaling can support either tissue repair or pathological remodeling depending on the physiological or disease context. This context-dependent nature of EGFR signaling provides the central framework of this review and offers a mechanistic basis for understanding why both EGFR activation and inhibition have produced beneficial effects in different experimental models of neurological disease. EGFR signaling pathway and its downstream cellular effects in the nervous system. EGFR signaling is initiated by binding of EGF-like ligands, including EGF, TGF-α, HB-EGF, betacellulin (BTC), amphiregulin (AREG), epiregulin (EREG), and epigen (EPGN). These ligands are generated through proteolytic cleavage (“shedding”) of membrane-bound precursors primarily by the metalloproteases ADAM10 and ADAM17. Ligand binding induces EGFR homo- or heterodimerization with other ErbB family members (ErbB2/3/4), resulting in receptor autophosphorylation and activation of downstream signaling cascades. Major downstream pathways include the RAS/RAF/MEK/ERK–MAPK, PI3K/AKT/mTOR, PLCγ/PKC, SRC, JNK, and JAK/STAT pathways, which regulate transcriptional programs involved in proliferation, survival, differentiation, migration, neurite outgrowth, angiogenesis, and remyelination. EGFR signaling is tightly regulated through receptor internalization, lysosomal degradation, dephosphorylation by protein tyrosine phosphatases, and negative feedback mechanisms. In neural repair contexts, EGFR activation engages pro-survival and regenerative pathways, principally the PI3K/AKT and MAPK/ERK cascades, which promote neuronal survival, neural progenitor proliferation, oligodendrocyte lineage expansion, remyelination, and tissue repair. In contrast, sustained or dysregulated EGFR activation can promote pathological responses through prolonged MAPK/ERK activity and activation of JAK/STAT signaling, contributing to neuroinflammation, astrogliosis, impaired proteostasis, and, in some contexts, excitotoxic injury. Thus, the functional consequences of EGFR signaling are determined not simply by receptor activation but by the cellular context and the duration, magnitude, and downstream integration of signaling. This figure was generated using BioRender.