Heparin-Binding Epidermal Growth Factor-Like Growth Factor as a New Target Molecule for Cancer Therapy

ErbB receptors belong to the tyrosine kinase family and consist of four ErbB members including EGFR/ErbB1, ErbB2, ErbB3, and ErbB4 [37, 40, 55] (Fig. 1). Activation of ErbB receptors is controlled by the spatiotemporally regulated expression and liberation of their ligands, which are members of the EGF family of growth factors. Ligand binding induces formation of homo- or heterodimeric complexes and activation of the intrinsic kinase domain, resulting in phosphorylation of specific tyrosine residues that serve as docking sites for adaptor molecules, which in turn leads to activation of intracellular signaling pathways. The EGF family of ligands is divided into four groups: (1) EGF, transforming growth factor-α (TGF-α), and amphiregulin, which bind to EGFR; (2) heparin-binding EGF-like growth factor (HB-EGF), epiregulin, epigen, and betacellulin, which bind to both EGFR and ErbB4; (3) neuregulin (NRG)1 and NRG2, which bind to ErbB3 and ErbB4; and (4) NRG3 and NRG4, which bind only to ErbB4, but not to ErbB3 (Fig. 1). ErbB receptors and their cognate ligands play fundamental roles in development, proliferation, and differentiation.