EGFR (ERBB1)
EGFR (epidermal growth factor receptor, ERBB1) is a receptor tyrosine kinase that converts extracellular growth signals into the RAS–MAPK and PI3K–AKT pathways inside the cell.
Function
EGF or a related ligand binds EGFR’s extracellular domain, the receptor dimerizes, and its intracellular kinase domains trans-phosphorylate each other on C-terminal tyrosines. Those phosphotyrosines dock the adapter proteins that launch two main cascades: the RAS–RAF–MEK–ERK kinase chain, which drives proliferation, and the PI3K–AKT route, which drives survival and growth. Ligand binding also triggers receptor internalization and lysosomal degradation, which limits how long the signal runs.
In cancer
EGFR is a proto-oncogene by every available route: amplification (glioblastoma, where the constitutively active EGFRvIII deletion variant is common), activating mutations in the kinase domain (a large fraction of lung adenocarcinomas in never-smokers), and overexpression (colorectal, head and neck). Each route makes the receptor signal without ligand. The kinase-domain mutations made EGFR the first solid-tumor target of a genotype-matched drug: gefitinib and erlotinib in EGFR-mutant lung cancer, cetuximab in colorectal cancer. Resistance arises through a second kinase-domain mutation (T790M) or through downstream KRAS activation, which bypasses the receptor entirely.
Notes
- Human gene symbol: EGFR; UniProt P00533; 1,210 amino acids; ERBB receptor family (with HER2, HER3, HER4).