ERBB3

ERBB3, also known as HER3, is a member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases. The ERBB3 gene encodes the protein and is located on chromosome 12 (12q13.2) in humans. The receptor is a single-pass transmembrane protein with an extracellular ligand-binding domain, a short transmembrane segment, and a cytoplasmic tail rich in tyrosine residues that serve as docking sites.

ERBB3 is characterized by very weak intrinsic kinase activity; thus it signals primarily through heterodimerization with other ERBB family members, especially ERBB2 (HER2). Its principal ligands are neuregulins (NRG1–NRG4), which bind to ERBB3 and/or ERBB4 to promote dimer formation. In the ERBB2–ERBB3 heterodimer, ERBB2 provides potent kinase activity, leading to phosphorylation of ERBB3 and recruitment of PI3K via its multiple p85-binding motifs. This activates the PI3K/Akt pathway, promoting cell survival and growth.

ERBB3 is expressed in various tissues and has roles in development, neural and cardiac signaling, and tissue repair. In cancer, ERBB3 overexpression, amplification, or ligand-dependent activation can contribute to tumor progression and resistance to therapies that target other ERBB receptors. As a result, ERBB3 is investigated as a therapeutic target, with antibodies and other agents designed to inhibit ERBB3 signaling or disrupt ERBB2–ERBB3 dimerization, often in combination with HER2-directed therapies.