EGFRERBBperhe

The EGFR/ERBB family, also known as the ERBB receptors or HER receptors, is a subfamily of receptor tyrosine kinases that regulate cellular growth, differentiation and survival. In humans, four members are enzymatic receptors: EGFR (ERBB1/HER1), ERBB2 (HER2), ERBB3 (HER3) and ERBB4 (HER4).

Activation occurs when ligands bind to the extracellular domain, promoting receptor dimerization (homo- or heterodimers) and autophosphorylation of cytoplasmic tyrosine residues. ERBB2 has no known direct ligand and is often the preferred dimerization partner; ERBB3 has impaired kinase activity and relies on dimerization for signaling. Ligands include EGF, transforming growth factor alpha (TGF-α), amphiregulin, epiregulin and betacellulin for EGFR; heregulins (neuregulins) preferentially activate ERBB3/ERBB4.

Downstream signaling engages pathways such as RAS-RAF-MEK-ERK and PI3K-AKT, with additional inputs from JAK/STAT and PKC, ultimately regulating proliferation, survival, differentiation and migration. Physiologically, ERBB signaling is important for development of the nervous system and heart, as well as skin homeostasis and tissue repair.

Dysregulation is common in cancer. ERBB2 amplification occurs in a substantial subset of breast cancers and correlates with aggressiveness. EGFR mutations and amplifications are observed in various tumors, notably non-small cell lung cancer and glioblastoma. Therapeutic strategies include monoclonal antibodies (e.g., trastuzumab and pertuzumab for ERBB2; cetuximab for EGFR) and tyrosine kinase inhibitors (e.g., lapatinib and afatinib for ERBB2/EGFR; osimertinib for EGFR-mutant NSCLC). Resistance and tumor heterogeneity pose clinical challenges, prompting ongoing research and combination approaches.