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

The Human epidermal growth factor receptor 2 (HER2) extracellular domain, domain II, is a specific structural region of the HER2 protein (also known as ErbB2) that is critical for receptor dimerization and downstream signaling (NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4131240/). Unlike other members of the ErbB family, HER2 has no known ligand and exists in a constitutively "open" conformation, leaving its dimerization arm in domain II always available for pairing with other receptors (Wikipedia, https://en.wikipedia.org/wiki/HER2). This domain is the primary site for the formation of HER2-HER3 heterodimers, which are the most potent activators of the PI3K/Akt and MAPK pathways that drive cell proliferation and survival (NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3654546/). In cancers such as HER2-positive breast and gastric cancer, the overexpression of HER2 leads to excessive dimerization and uncontrolled tumor growth (NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5635244/). The monoclonal antibody pertuzumab specifically binds to an epitope within domain II, sterically blocking the dimerization arm and preventing the formation of signaling-active complexes (Patsnap, https://patsnap.com). This mechanism is distinct from and complementary to that of trastuzumab, which targets domain IV of the same receptor (NIH, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3654546/). In addition to blocking signaling, drugs targeting this domain can induce antibody-dependent cellular cytotoxicity (ADCC) to further eliminate cancer cells (Patsnap, https://patsnap.com). Clinical management of therapies targeting this domain requires monitoring for potential cardiotoxicity and embryo-fetal toxicity (Komen, https://www.komen.org).

Other names

ErbB2 domain IICD340 domain IINeu domain IIHER2 dimerization domainHER2 subdomain II

Inhibition of receptor dimerization and induction of antibody-dependent cellular cytotoxicity (ADCC)