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

The Human epidermal growth factor receptor 2 (HER2) extracellular domain IV is a critical structural region of the HER2 protein, a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases. Unlike other members of its family, HER2 exists in a constitutively 'active' or open conformation and has no known high-affinity ligand, making it the preferred dimerization partner for other ErbB receptors. Domain IV is located juxtamembrane and is the specific epitope targeted by the therapeutic antibody trastuzumab. Binding to this domain inhibits the shedding of the extracellular domain, a process that otherwise generates a truncated, highly oncogenic p95 fragment. In many cancers, particularly breast and gastric malignancies, HER2 is overexpressed or the gene is amplified, leading to uncontrolled cell growth and survival. Therapeutic targeting of Domain IV not only disrupts oncogenic signaling through the PI3K and MAPK pathways but also recruits immune effector cells to induce antibody-dependent cellular cytotoxicity (ADCC) against the tumor cells.

Other names

ERBB2 Domain IVNEU Domain IVCD340 Domain IVReceptor tyrosine-protein kinase erbB-2 extracellular domain IVProto-oncogene Neu Domain IV

Binding to Domain IV prevents the proteolytic cleavage of the extracellular domain (shedding) which would otherwise leave a constitutively active p95HER2 fragment; it also mediates antibody-dependent cellular cytotoxicity (ADCC) and inhibits downstream MAPK and PI3K/Akt signaling pathways.