| HER3/ErbB3 is a catalytically inactive “pseudokinase” member of the ErbB/HER receptor tyrosine kinase family, rendered intrinsically inactive by key substitutions in its kinase domain but capable of robust signaling through heterodimerization with active family members such as HER2 or EGFR. HER3 comprises an extracellular domain (ECD) with four subdomains: leucine-rich I/III for high-affinity neuregulin (NRG1/2) binding and cysteine-rich II/IV, with subdomain II harboring a dimerization arm; a single transmembrane α-helix; a juxtamembrane region; an atypical kinase domain (shortened αC-helix, inactive configuration despite ATP binding); and a C-terminal tail containing at least 9–11 tyrosine sites (notably Tyr1222 and Tyr1289 in YXXM motifs) for adaptor docking. Upon ligand binding, HER3’s ECD undergoes a conformational change that exposes the dimerization loop, promoting asymmetric heterodimer formation, most potently with HER2, whereby the partner’s kinase activity trans-phosphorylates HER3’s tyrosines. These phosphorylated tyrosines recruit PI3K p85 (via YXXM motifs), Grb2/Shc (MAPK/ERK), and Src, activating pathways for cell survival and proliferation. HER3 is crucial for organogenesis (nervous and cardiac development), drives cancer progression notably in breast, ovarian, and lung cancers, and mediates resistance to EGFR/HER2 inhibitors through compensatory signaling. |
