EGFRs

The EGFRs, or epidermal growth factor receptors, are a subset of receptor tyrosine kinases in the ErbB/HER family. The family includes four members: EGFR (ERBB1/HER1), ERBB2 (HER2), ERBB3 (HER3), and ERBB4 (HER4). ERBB2 lacks a direct ligand, and ERBB3 has limited kinase activity; all can form homo- or heterodimers upon activation.

They are single-pass transmembrane proteins with an extracellular ligand-binding domain, a transmembrane segment, and an intracellular tyrosine kinase domain (except ERBB3). Ligands such as EGF, transforming growth factor-alpha, and neuregulins bind to the extracellular domain, promoting dimerization and autophosphorylation of tyrosine residues.

Activated receptors recruit signaling proteins and trigger cascades including RAS-RAF-MEK-ERK, PI3K-AKT-mTOR, PLCγ, and JAK-STAT, controlling cell proliferation, survival, differentiation, and migration. They play roles in development and tissue homeostasis; dysregulation is implicated in cancer.

Clinically, EGFR signaling is altered in many cancers. EGFR and HER2 are common targets: TKIs such as gefitinib, erlotinib, and afatinib; monoclonal antibodies such as cetuximab and panitumumab; HER2-directed therapies like trastuzumab. Resistance is common, with mechanisms including secondary mutations (e.g., EGFR T790M), bypass signaling, and histologic transformation.

In research and diagnostics, EGFR status informs prognosis and therapy choices, especially in non-small cell lung cancer and breast cancer. The signaling network of the EGFR family is a focus of studies on receptor dimerization, ligand specificity, and cross-talk with other pathways.