Receptor tyrosine-protein kinase erbB-2 (HER2) extracellular domain subdomain IV (HER2 ECD Subdomain IV)

The HER2 (Human Epidermal Growth Factor Receptor 2) extracellular domain (ECD) is a critical structural component of the HER2 receptor, a member of the ErbB family of receptor tyrosine kinases [2, 3, 5]. Subdomain IV of the ECD is located proximal to the cell membrane and serves as the specific binding site for the therapeutic monoclonal antibody trastuzumab and its derivatives [2, 4, 8]. Unlike other members of the EGFR family, HER2 does not have a known ligand and exists in a constitutively active "open" conformation, making it the preferred dimerization partner for other HER receptors [2, 4, 10]. Subdomain IV plays a vital role in stabilizing these dimers and is the site of proteolytic cleavage (shedding), which can result in the formation of a constitutively active p95HER2 fragment [1, 4, 7]. Overexpression or amplification of HER2 leads to uncontrolled cell proliferation and survival, driving the progression of various cancers, most notably HER2-positive breast and gastric cancers [8, 9, 11]. Drugs targeting subdomain IV work by inhibiting ligand-independent dimerization, preventing receptor shedding, and inducing antibody-dependent cellular cytotoxicity (ADCC), thereby blocking downstream oncogenic signaling pathways like PI3K/Akt and MAPK [1, 2, 8, 10]. This targeted approach has significantly improved outcomes for patients with HER2-positive malignancies, although resistance and cardiotoxicity remain important clinical challenges [13, 15].

Other names

HER2 domain IVErbB2 domain IVTrastuzumab binding siteHER2 DIVCD340 domain IVProto-oncogene Neu domain IV

Trastuzumab and its derivatives bind to subdomain IV of the HER2 extracellular domain, which inhibits ligand-independent dimerization, prevents the proteolytic cleavage (shedding) of the extracellular domain, and induces antibody-dependent cellular cytotoxicity (ADCC) [1, 4]. This binding leads to the downregulation of the HER2 receptor and the inhibition of downstream signaling pathways, including the PI3K/Akt and MAPK pathways, ultimately suppressing cell proliferation and survival [1, 2, 8].