Human epidermal growth factor receptor 2 (HER2) extracellular domain subdomain II (HER2 ECD Subdomain II)

Human epidermal growth factor receptor 2 (HER2), also known as ErbB2, is a transmembrane receptor tyrosine kinase and a member of the epidermal growth factor receptor (EGFR) family [3, 12]. Unlike other members of this family, HER2 does not bind to any known ligands and exists in a constitutively active, open conformation [8, 14]. The extracellular domain of HER2 is divided into four subdomains (I-IV), with subdomain II containing a critical dimerization arm that facilitates protein-protein interactions [6, 11]. This subdomain is essential for HER2 to form heterodimers with other ligand-activated ErbB receptors, such as HER3, which triggers potent downstream signaling through the PI3K/Akt and MAPK pathways [1, 4]. In various malignancies, most notably breast and gastric cancers, HER2 is frequently overexpressed or gene-amplified, driving uncontrolled cell proliferation and survival [13, 15]. Subdomain II is the specific binding site for the monoclonal antibody pertuzumab, which sterically blocks the dimerization arm to prevent receptor pairing and subsequent oncogenic signaling [2, 5]. Targeting this specific region provides a synergistic effect when combined with other HER2-directed therapies that bind to different domains, such as trastuzumab [4, 16].

Other names

ErbB2 subdomain IINeu subdomain IICD340 subdomain IIHER2 dimerization domainHER2 dimerization arm

Inhibition of ligand-dependent HER2 heterodimerization with other ErbB family members (EGFR, HER3, and HER4) by sterically blocking the dimerization arm in subdomain II [1, 2, 4].