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

Receptor tyrosine-protein kinase erbB-2 (HER2), also known as CD340 or Neu, is a member of the epidermal growth factor receptor (EGFR/ErbB) family of receptor tyrosine kinases (UniProt P04626). Unlike other ErbB members, HER2 has no known high-affinity ligand and exists in a constitutively active, 'open' conformation, making it the preferred dimerization partner for other ligand-bound ErbB receptors (Yarden and Sliwkowski, Nature Reviews Cancer 2001). Extracellular domain IV (ECD IV) is the C-terminal region of the HER2 extracellular portion, located closest to the cell membrane, and serves as the specific binding epitope for the monoclonal antibody trastuzumab (Cho et al., Nature 2003). Overexpression or gene amplification of HER2 occurs in approximately 15-30% of breast cancers and is associated with aggressive tumor growth and poor clinical prognosis (Slamon et al., Science 1987). Therapeutic targeting of domain IV disrupts oncogenic signaling pathways such as PI3K/AKT and MAPK, while also facilitating immune-mediated destruction of cancer cells. Clinical management of HER2-positive malignancies relies heavily on drugs targeting this specific domain, though monitoring for potential cardiotoxicity remains a critical safety requirement (FDA Herceptin Label).

Other names

ErbB2NeuCD340Proto-oncogene NeuHuman epidermal growth factor receptor 2MLN 19T6-16

Binding to domain IV inhibits HER2-mediated signaling by preventing the shedding of the extracellular domain (which would otherwise create the constitutively active p95 fragment), blocking ligand-independent signaling, and inducing antibody-dependent cellular cytotoxicity (ADCC) through the recruitment of immune effector cells (Cho et al., Nature 2003; Yarden and Sliwkowski, Nature Reviews Cancer 2001).