Human epidermal growth factor receptor 2 (HER2) extracellular domain I (HER2 ECD I)

Human epidermal growth factor receptor 2 (HER2), also known as ErbB2 or CD340, is a member of the epidermal growth factor receptor (EGFR/ErbB) family of receptor tyrosine kinases [1]. The extracellular region of HER2 is composed of four distinct domains (I-IV), with Domain I being a leucine-rich segment located at the N-terminus [2]. Unlike other ErbB family members, HER2 does not have a known high-affinity ligand and exists in a constitutively "open" or active conformation, allowing it to readily heterodimerize with other ligand-bound ErbB receptors [4]. Domain I, along with Domain III, forms the structural equivalent of a ligand-binding pocket, though in HER2 this pocket is non-functional for traditional ligands [2]. While established therapies like Trastuzumab and Pertuzumab target Domains IV and II respectively, Domain I has emerged as a target for novel therapeutic agents, such as the bispecific antibody MM-111, which aims to block HER2/HER3 heterodimerization [3]. Overexpression of HER2 leads to hyperactivation of the PI3K/AKT and MAPK pathways, driving the progression of various malignancies, most notably breast and gastric cancers [5]. Consequently, targeting specific extracellular domains like Domain I provides a strategy to overcome resistance to existing HER2-targeted therapies by disrupting alternative signaling interfaces.

Other names

ErbB2 domain ICD340 domain INeu domain IReceptor tyrosine-protein kinase erbB-2 domain IProto-oncogene Neu domain I

Binding to the extracellular domain I prevents the formation of active signaling complexes, particularly HER2/HER3 heterodimerization, thereby inhibiting downstream oncogenic signaling pathways such as PI3K/AKT and MAPK, and potentially inducing antibody-dependent cellular cytotoxicity (ADCC) [3, 6].