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

Receptor tyrosine-protein kinase erbB-2 (ERBB2), also known as HER2, is a member of the epidermal growth factor receptor (EGFR) family. Unlike other members of its family, ERBB2 does not have a known high-affinity ligand and remains in an open, constitutively active conformation ready for dimerization (UniProt P04626). The extracellular domain II (ECD II) contains the dimerization arm, which is essential for the formation of heterodimers with other ErbB family members, particularly HER3, which is a potent activator of the PI3K/AKT signaling pathway (PubMed: 12447385). Overexpression or amplification of ERBB2 is a well-documented driver in various malignancies, most notably breast and gastric cancers, leading to uncontrolled cell growth and survival. The monoclonal antibody pertuzumab specifically targets ECD II, sterically hindering the dimerization process and inhibiting downstream oncogenic signaling (FDA: Perjeta Label). This domain-specific targeting is often used in combination with other HER2-targeted therapies, such as trastuzumab which binds domain IV, to achieve more comprehensive blockade of the receptor's activity and improve clinical outcomes in HER2-positive patients. Newer agents like the bispecific antibody zanidatamab also target this domain to enhance receptor internalization and signaling inhibition (PubMed: 30224336).

Other names

HER2 domain IIErbB2 domain IIHuman epidermal growth factor receptor 2 domain IINEU domain IICD340 domain IIp185erbB2 domain II

Inhibition of ligand-dependent heterodimerization (primarily HER2-HER3) by binding to the dimerization arm in extracellular domain II, thereby blocking downstream signaling pathways such as PI3K/AKT and MAPK, and inducing antibody-dependent cellular cytotoxicity (ADCC) (PubMed: 12447385, FDA: Perjeta Label). Bispecific agents may also induce receptor clustering and internalization (PubMed: 30224336).