Human epidermal growth factor receptor 2 (HER2) subdomain IV (HER2 subdomain IV)

Human epidermal growth factor receptor 2 (HER2), also known as ErbB2, is a transmembrane receptor tyrosine kinase belonging to the epidermal growth factor receptor (EGFR) family (UniProt P04626). Subdomain IV is a specific cysteine-rich region within the extracellular domain (ECD) of HER2, located proximal to the plasma membrane. Unlike other ErbB receptors, HER2 lacks a known high-affinity ligand and exists in a constitutively active conformation, making it a potent partner for heterodimerization with other ErbB members. Subdomain IV is clinically significant as the specific binding epitope for the monoclonal antibody trastuzumab (Herceptin) (Cho et al., 2003, Nature). Binding to this subdomain inhibits HER2 signaling by preventing the proteolytic cleavage of the ECD (which would otherwise leave a constitutively active p95 fragment) and blocking ligand-independent dimerization. Furthermore, the binding of antibodies to this region facilitates the recruitment of immune effector cells to mediate antibody-dependent cellular cytotoxicity (ADCC). HER2 overexpression is a major oncogenic driver in approximately 15-30% of breast cancers and various other solid tumors, making subdomain IV a critical focal point for targeted biologics and antibody-drug conjugates (NIH, National Cancer Institute).

Other names

ErbB2 domain IVHER2 extracellular domain IVTrastuzumab binding sitep185 subdomain IVCD340 subdomain IV

Binding to subdomain IV inhibits the proteolytic shedding of the HER2 extracellular domain, prevents ligand-independent HER2 dimerization and downstream PI3K/AKT signaling, and mediates antibody-dependent cellular cytotoxicity (ADCC).