Erb-B2 receptor tyrosine kinase 2 (ERBB2) (ERBB2)

Erb-B2 receptor tyrosine kinase 2 (ERBB2), commonly known as HER2, is a transmembrane glycoprotein and a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases [1]. It is unique among the EGFR family because it lacks a known high-affinity ligand and remains in an open, active conformation, allowing it to readily heterodimerize with other ligand-bound EGFR members to initiate potent downstream signaling [1, 2]. Domain IV is the juxtamembrane region of the extracellular domain and serves as the specific epitope for the therapeutic monoclonal antibody trastuzumab [2]. Targeting domain IV is clinically significant as it prevents the proteolytic cleavage (shedding) of the extracellular domain, which would otherwise result in a constitutively active truncated receptor known as p95HER2 [3, 4]. Furthermore, drugs binding to this domain inhibit the PI3K/Akt and MAPK pathways and recruit immune effector cells to mediate antibody-dependent cellular cytotoxicity (ADCC) [4]. ERBB2 is frequently overexpressed or amplified in approximately 15-30% of breast cancers and is also a key driver in gastric and esophageal cancers, where it is associated with aggressive disease and poor prognosis [3, 5].

Other names

HER2Human epidermal growth factor receptor 2NEUCD340Proto-oncogene NeuMLN 19Receptor tyrosine-protein kinase erbB-2ERBB2 domain IV

Binding to the extracellular domain IV of ERBB2 to inhibit ligand-independent signaling, prevent extracellular domain shedding, and induce antibody-dependent cellular cytotoxicity (ADCC) [2, 4].