Abstract
This chapter reviews the family of receptors as ErbB receptors and the individual receptors, such as EGFR (epidermal growth factor receptor), HER2 (human epidermal growth factor receptor 2), HER3, or HER4. The soluble extracellular regions of these receptors are referred to as sEGFR, sHER2, sHER3, and sHER4. Both EGF and EGFR are archetypes of protein families that have undergone duplication and diversification throughout animal evolution. EGF-related ligands include EGF, transforming growth factor-α (TGFα), heparin-binding EGF-like growth factor (HB-EGF), amphiregulin, betacellulin, and several isoforms of heregulin/neuregulin. The association of ErbB receptors with human disease is also discussed. HER2 presents a particularly instructive example of growth factor receptor involvement in cancer. All structures of ErbB extracellular domains confirm the expected structural homology of the ‘L’ domains (domains I and III) to one another and to corresponding domains in type I insulin-like growth factor receptor (IGF1R). The structure of entire ErbB receptor ectodomains is provided. The structure of a complex of the EGFR extracellular region and EGF determined at low pH provides a snapshot of a likely mechanism for release of bound ligand in the low pH environment of the endosome. HER2 is unique among ErbB receptors in that no high-affinity HER2 ligand has been found, it functions as a co-receptor with each of the other ErbB receptors and transforms when overexpressed. The active-like structure of HER2 provides a structural basis for its role as the preferred heterodimerization partner among ErbB receptors.
Published Version
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