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

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]. Domain IV of the HER2 extracellular domain (ECD) is a cysteine-rich region located proximal to the cell membrane that serves as a critical structural component for receptor stability and signaling [PMID: 12150910]. Unlike other members of the ErbB family, HER2 lacks a known high-affinity ligand and exists in a constitutively "active" conformation, making it the preferred heterodimerization partner for other ligand-activated ErbB receptors [NCBI: Gene ID 2064]. This dimerization triggers intracellular signaling cascades, primarily the PI3K/Akt and MAPK pathways, which promote cell proliferation, survival, and angiogenesis [PMID: 15254673]. In various malignancies, most notably breast and gastric cancers, HER2 is frequently overexpressed or the ERBB2 gene is amplified, driving aggressive tumor growth [PMID: 10805225]. Domain IV is the specific binding site for the monoclonal antibody trastuzumab and its derived antibody-drug conjugates (ADCs) [PMID: 12150910]. Therapeutic targeting of this domain inhibits the proteolytic cleavage (shedding) of the ECD—which would otherwise leave a constitutively active p95 fragment—and facilitates antibody-dependent cellular cytotoxicity (ADCC) by recruiting immune effector cells [PMID: 19056901]. Clinical management of HER2-positive diseases relies on the precise assessment of HER2 status via immunohistochemistry or in situ hybridization to guide the use of these Domain IV-targeted therapies [ASCO/CAP Guidelines].

Other names

ERBB2CD340Proto-oncogene Neup185erbB2NEUReceptor tyrosine-protein kinase erbB-2HER2 Domain IV

Binding to Domain IV of the HER2 extracellular domain inhibits proteolytic shedding of the receptor, prevents ligand-independent dimerization, suppresses downstream PI3K/Akt signaling, and mediates antibody-dependent cellular cytotoxicity (ADCC) [PMID: 12150910, PMID: 10805225].