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

The Human epidermal growth factor receptor 2 (HER2) extracellular domain subdomain IV is a specific structural region of the HER2 receptor tyrosine kinase, located near the cell membrane [1]. Unlike other members of the ErbB family, HER2 exists in a constitutively active conformation, allowing it to dimerize without a direct ligand [3]. Subdomain IV is the specific epitope targeted by the monoclonal antibody Trastuzumab and its derivatives [2]. Binding to this region inhibits the proteolytic shedding of the extracellular domain, which prevents the formation of the highly active p95 truncated receptor [5]. Additionally, targeting this subdomain disrupts ligand-independent signaling and facilitates immune-mediated destruction of overexpressing tumor cells through antibody-dependent cellular cytotoxicity [2][4]. This target is a cornerstone in the treatment of HER2-positive malignancies, particularly in breast and gastric cancers.

Other names

ErbB2 subdomain IVHER2 domain IVCD340 subdomain IVp185 subdomain IVProto-oncogene Neu subdomain IV

Therapeutic antibodies bind to subdomain IV to inhibit the proteolytic cleavage (shedding) of the extracellular domain, thereby preventing the formation of the constitutively active p95 fragment [1][2]. This binding also inhibits ligand-independent HER2 dimerization and downstream signaling pathways like PI3K/Akt, while simultaneously recruiting immune effector cells to mediate antibody-dependent cellular cytotoxicity (ADCC) [3][4].