Human epidermal growth factor receptor 2 (HER2) extracellular domain, subdomain II (HER2 ECD Subdomain II)

The Human epidermal growth factor receptor 2 (HER2) extracellular domain, subdomain II, is a critical structural region of the HER2 protein, which belongs to the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases [1]. Unlike other members of the ErbB family, HER2 does not have a known high-affinity ligand and exists in a 'fixed' or 'open' conformation that is constitutively ready for dimerization [2]. Subdomain II, often referred to as the dimerization arm, is essential for the formation of heterodimers with other ErbB receptors, particularly HER3, which initiates potent downstream signaling through the PI3K/Akt and MAPK pathways [2,3]. In various malignancies, most notably HER2-positive breast and gastric cancers, the overexpression of HER2 leads to excessive dimerization and uncontrolled cell proliferation [4]. This specific subdomain is the therapeutic target of the monoclonal antibody Pertuzumab, which binds to the dimerization arm and sterically hinders the receptor's ability to pair with other HER family members [3,5]. By blocking these protein-protein interactions at subdomain II, targeted therapies can effectively inhibit oncogenic signaling and improve survival outcomes in patients with HER2-driven tumors [5]. Sources: [1] UniProt Consortium. (2023). UniProtKB - P04626 (ERBB2_HUMAN). [2] Franklin, M. C., et al. (2004). Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell, 5(4), 317-328. [3] U.S. Food and Drug Administration. (2012). Perjeta (pertuzumab) Prescribing Information. [4] National Cancer Institute. (2023). HER2-Positive Breast Cancer. [5] Baselga, J., & Swain, S. M. (2009). Novel anticancer targets: revisiting ERBB2 and discovering ERBB3. Nature Reviews Cancer, 9(7), 463-475.

Other names

ErbB2 subdomain IICD340 subdomain IINeu subdomain IIReceptor tyrosine-protein kinase erbB-2 extracellular domain IIHER2 dimerization arm

Inhibition of HER2 heterodimerization by sterically blocking the dimerization arm in subdomain II, preventing interaction with other ErbB family members (e.g., HER3).