Heparin-binding EGF-like growth factor (HB-EGF) is a 1216 kDa member of the epidermal growth factor (EGF) family. It possesses an EGFlike domain, and a heparin-binding motif. Mature HBEGF is a soluble peptide that arises from proteolytic processing of the transmembrane form. Human HBEGF shows 76% and 73% aa sequence identity with rat and mouse HBEGF, respectively. It is required for normal cardiac valve formation and normal heart function, promotes smooth muscle cell proliferation. It may be involved in macrophage-mediated cellular proliferation; it is mitogenic for fibroblasts, but not endothelial cells. HBEGF classified as a group 2 ErbB ligand based on its ability to activate both the EGF/ErbB1 and ErbB4 receptors. Activity associated with ErbB4 binding appears to be limited to nonmitogenic actions, while EGFR binding induces both mitogenic and nonmitogenic activity.