Receptor tyrosine-protein kinase erbB-2 domain IV (HER2 domain IV)

HER2 domain IV is the membrane-proximal subregion of the extracellular domain of human receptor tyrosine-protein kinase erbB-2 (HER2/ERBB2), a key oncogenic driver widely implicated in human cancers, especially breast cancer[4]. The HER2 extracellular domain comprises four subdomains (I–IV). Domain IV, although lacking direct ligand binding ability, plays an important structural role; it is involved in stabilization of receptor dimerization interfaces with partner HER family receptors (such as EGFR and HER3)[4][5]. Structural studies show domain IV largely consists of β-strands, loops, and disulfide bonds, and antibodies targeting domain IV, such as trastuzumab, disrupt dimerization and downstream oncogenic signaling[7]. Therapeutic targeting of HER2 domain IV—currently an established site for monoclonal antibody intervention—has transformed the prognosis of HER2-positive cancers, but also entails notable risks such as cardiotoxicity and acquired resistance[2][4][7].

Other names

HER2 extracellular domain IVERBB2 domain IVNeu domain IV

Antibody binding to domain IV can block receptor dimerization, leading to inhibition of downstream signaling (e.g., by Trastuzumab); Direct inhibition or destabilization of HER2/HER2 or HER2/partner receptor dimer formation; Promotion of receptor internalization and immune-mediated cytotoxicity