Receptor tyrosine-protein kinase erbB-2 (ERBB2) domain II (ERBB2 domain II)

Receptor tyrosine-protein kinase erbB-2 (ERBB2), also known as HER2, is a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases [1]. Domain II of the ERBB2 extracellular region is the dimerization domain, which contains the 'dimerization arm' (residues 190–209) essential for forming heterodimers with other ErbB receptors, particularly HER3 [4]. Unlike other family members, ERBB2 has no known high-affinity ligand and exists in a constitutively 'active' conformation, making it the preferred dimerization partner for other ErbB receptors [1, 4]. Overexpression or amplification of ERBB2 is a major driver in several malignancies, including breast and gastric cancers, leading to uncontrolled cell proliferation and survival signaling [2, 3]. Therapeutic targeting of Domain II, most notably by the monoclonal antibody pertuzumab, sterically inhibits the formation of HER2-HER3 heterodimers, thereby blocking downstream oncogenic signaling pathways like PI3K/Akt [2, 4]. This domain-specific inhibition is distinct from the mechanism of trastuzumab, which binds to Domain IV, allowing for synergistic effects when used in combination therapy [3]. References: [1] UniProt (P04626); [2] FDA Label (Perjeta); [3] Baselga et al. (2012) NEJM; [4] Franklin et al. (2004) Cancer Cell.

Other names

HER2 domain IIErbB2 extracellular domain IICD340 domain IINEU domain IIProto-oncogene Neu domain II

Inhibition of ligand-induced heterodimerization with other ErbB family members (primarily HER3) by binding to the dimerization arm in the extracellular domain II [2, 4].