ErbB4/HER4

The receptor tyrosine-protein kinase ErbB4 (HER4) is a member of the epidermal growth factor receptor (EGFR) family, which also includes EGFR (ErbB1), ErbB2 (HER2/neu), and ErbB3 (HER3). The EGFR family members regulate cellular proliferation, differentiation, and programmed cell death in a growth factor-dependent manner. Similar to other RTKs, ligand interaction with ErbB4 promotes receptor dimerization, kinase activation, and initiation of phosphorylation-dependent signaling cascades, such as the mitogen-activated protein kinase (MAPK) and PI3-K/Akt cascades. ErbB4 is a fully functional RTK capable of signaling, both as a homo- as well as a heterodimer. It can be activated by at least seven members of EGF-related peptide growth factors: the neuregulins (NRG-1, NRG-2, NRG-3, and NRG-4), heparin-binding EGF-like growth factor (HB-EGF), betacellulin (BTC) and epiregulin (ER). In addition, unlike the other ERBB members, ErbB4 has been demonstrated undergo regulated intramembrane proteolysis (RIP), resulting in generation of a soluble intracellular domain (ICD). The released ErbB4 ICD is able to translocate to the nucleus and regulate transcription. ErbB4 and its ligands may have important roles in normal cardiovascular and neural development, differentiation of the mammary gland, and in pathological conditions, such as heart diseases and cancer.