ErbB2–ErbB3 heterodimeric receptor (ERBB2/ERBB3)

The ErbB2–ErbB3 heterodimeric receptor is a complex formed by the dimerization of two members of the epidermal growth factor receptor (EGFR/ErbB) family: ErbB2 (HER2) and ErbB3 (HER3). ErbB2 possesses intrinsic receptor tyrosine kinase activity but has no known ligand, while ErbB3 binds growth factors such as neuregulins (NRG1, NRG2) but lacks effective kinase activity itself[1][3][4][6]. Dimerization, usually triggered by ligand binding to ErbB3, brings these receptors together, allowing ErbB2 to phosphorylate multiple tyrosine residues in ErbB3’s C-terminal tail, thereby initiating potent downstream signaling, most notably through the PI3K/AKT and RAS/MAPK proliferation and survival pathways[1][2][4][5][6][7]. This heterodimer delivers the most mitogenically potent signal among the ErbB receptor combinations and is essential for the proliferation of HER2-driven cancers, especially breast cancer. Therapeutics targeting this complex include monoclonal antibodies (e.g., trastuzumab, pertuzumab) and kinase inhibitors (e.g., lapatinib), which block heterodimer formation, receptor activation, or downstream signaling[2][4][5][6]. Overexpression or amplification of HER2 and activation of the ERBB2–ERBB3 heterodimer are strongly implicated as drivers of oncogenesis and tumor progression in several cancers, and their presence serves as a biomarker for patient selection and response to targeted therapy. Key therapeutic challenges include the development of drug resistance and safety concerns such as cardiotoxicity[6][7].

Other names

HER2–HER3 heterodimerErbB-2–ErbB-3 heterodimerHER2/HER3 dimer

Inhibition of dimerization (e.g., pertuzumab prevents HER2/HER3 dimer formation); Inhibition of tyrosine kinase activity (e.g., lapatinib inhibits HER2 and EGFR kinase activity); Antibody-dependent cellular cytotoxicity (trastuzumab, margetuximab); Downregulation of receptor expression (some antibodies induce receptor internalization or degradation); Downstream signaling blockade (inhibition of AKT and MAPK pathways)