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

Human epidermal growth factor receptor 2 (HER2), encoded by the ERBB2 gene, is a transmembrane receptor tyrosine kinase and a member of the EGFR/ErbB family (UniProt: P04626). The extracellular domain II (ECD II) of HER2 is a critical structural component known as the "dimerization arm," which facilitates the formation of heterodimers with other ErbB receptors, most notably HER3 (Franklin et al., 2004, Cancer Cell). Unlike other family members, HER2 exists in an "always open" conformation, making ECD II essential for ligand-independent signaling that drives cell proliferation and survival via the PI3K/AKT and MAPK pathways (PubMed: 15030714). In clinical oncology, HER2 overexpression or gene amplification is a major driver of aggressive breast and gastric cancers (StatPearls: HER2). The therapeutic monoclonal antibody pertuzumab (Perjeta) specifically binds to ECD II, sterically inhibiting the dimerization process and suppressing downstream oncogenic signaling (FDA Label: Perjeta). This mechanism complements other therapies like trastuzumab, which binds to domain IV, providing a more comprehensive blockade of HER2-mediated disease progression.

Other names

ERBB2 domain IIHER2 dimerization domainReceptor tyrosine-protein kinase erbB-2 domain IINEU domain IICD340 domain II

Pertuzumab binds to the extracellular dimerization domain (domain II) of HER2, sterically blocking its ability to pair with other ErbB family members, particularly HER3 (FDA Label: Perjeta). This inhibition prevents the activation of downstream signaling pathways such as PI3K/AKT and MAPK, which are vital for tumor cell growth (PubMed: 15030714). Additionally, the drug facilitates antibody-dependent cellular cytotoxicity (ADCC) to recruit immune cells to the tumor site.