Human epidermal growth factor receptor 2 (extracellular domain IV) (HER2 (extracellular domain IV))

The human epidermal growth factor receptor 2 (HER2, also called ERBB2) is a member of the ErbB family of receptor tyrosine kinases and is composed of an extracellular domain (ECD) subdivided into four subdomains (I–IV), a single transmembrane domain, and an intracellular kinase domain[1][2][3][4]. Extracellular domain IV is the region closest to the membrane and plays a structural role in stabilizing protein-protein interactions, particularly between HER2 and its dimerization partners[3]. Although its mechanistic contribution to ligand binding and dimer formation is less well understood than other domains, structural analysis shows that domain IV consists predominantly of β-strand and loop structures, stabilized by disulfide bonds, and is the main epitope for the therapeutic antibody trastuzumab[3][4][5]. HER2 overexpression or gene amplification is a major oncogenic driver in various cancers—especially breast, gastric, and ovarian cancer—making it a critical biomarker and therapeutic target. Drugs targeting the HER2 extracellular domain IV, such as trastuzumab, bind to this region to block dimerization-driven downstream signaling, resulting in tumor cell growth inhibition and immune-mediated cytotoxicity[3][4][5]. Persistent activation of HER2, often due to overexpression or mutation, leads to uncontrolled proliferation, aggressive tumor behavior, and poor clinical outcome. Trastuzumab and related drugs exploit these structural and functional features for clinical benefit.

Other names

ERBB2 (extracellular domain IV)HER2/Neu (extracellular domain IV)Receptor tyrosine-protein kinase erbB-2 (extracellular domain IV)

Inhibition of HER2 dimerization and signaling by blocking extracellular interactions; Downregulation of HER2 surface expression; Induction of antibody-dependent cellular cytotoxicity (ADCC)