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

Receptor tyrosine-protein kinase erbB-2 (HER2) is a member of the epidermal growth factor receptor (EGFR) family that plays a pivotal role in cell growth, differentiation, and survival [1]. Unlike other ErbB family members, HER2 does not have a known high-affinity ligand and remains in an "open" conformation ready for dimerization [2]. Extracellular domain II (ECD II) contains the dimerization arm, which is essential for HER2 to form heterodimers with other ligand-activated receptors, such as HER3 or HER1 (EGFR) [2]. This dimerization leads to the activation of intracellular tyrosine kinase domains and subsequent signaling through the PI3K/AKT and Ras/Raf/MEK/ERK pathways [1, 2]. In many cancers, HER2 is overexpressed or amplified, leading to constitutive signaling and aggressive tumor behavior [3]. Therapeutic targeting of ECD II, specifically by the monoclonal antibody pertuzumab, prevents the dimerization process, thereby inhibiting oncogenic signaling [2, 4]. This mechanism provides a synergistic effect when used with other HER2-targeted therapies like trastuzumab, which binds to domain IV [3, 4]. Clinical use of these agents has significantly improved outcomes in HER2-positive breast and gastric cancers [4].

Other names

Human epidermal growth factor receptor 2 domain IIHER2 subdomain IIERBB2 domain IIp185erbB2 domain IINEU domain II

Inhibition of ligand-induced heterodimerization (primarily HER2-HER3) by binding to the dimerization arm in extracellular domain II, thereby blocking downstream oncogenic signaling pathways such as PI3K/AKT and MAPK, and inducing antibody-dependent cellular cytotoxicity (ADCC) [2, 3].