Receptor tyrosine-protein kinase erbB-2 (ERBB2) extracellular domain IV (ERBB2 ECD IV)

Receptor tyrosine-protein kinase erbB-2 (ERBB2), commonly known as HER2, is a transmembrane receptor tyrosine kinase and a member of the epidermal growth factor receptor (EGFR) family (UniProt: P04626). It is unique among the ErbB family because it lacks a known high-affinity ligand and remains in an open conformation, allowing it to readily heterodimerize with other ErbB receptors to initiate potent downstream signaling via the PI3K/Akt and MAPK pathways (PubMed: 29439119). The extracellular domain IV (ECD IV) is the juxtamembrane region of the receptor and serves as the specific binding site for the therapeutic antibody trastuzumab (PubMed: 12192401). Overexpression or amplification of ERBB2 is a major driver in approximately 20% of breast cancers and is also prevalent in gastric and gastroesophageal junction cancers (NIH: StatPearls). Targeting ECD IV with monoclonal antibodies or antibody-drug conjugates inhibits oncogenic signaling, prevents the formation of the truncated p95HER2 fragment, and induces immune-mediated tumor cell death (DrugBank: DB00072). Clinical management of ERBB2-positive cancers relies heavily on agents targeting this domain, though resistance and cardiotoxicity remain significant therapeutic challenges (PubMed: 22371114).

Other names

HER2 Domain IVERBB2 ECD IVTrastuzumab binding siteHER2 juxtamembrane domainHuman epidermal growth factor receptor 2NEUCD340

Binding to the extracellular domain IV (ECD IV) of ERBB2 inhibits ligand-independent dimerization and prevents the proteolytic cleavage (shedding) of the extracellular domain, which would otherwise leave a constitutively active p95 fragment. It also mediates antibody-dependent cellular cytotoxicity (ADCC) by recruiting immune effector cells to the tumor site (PubMed: 12192401, DrugBank: DB00072).