The EGF receptor family comprises several related receptor tyrosine kinases that are frequently overexpressed in a variety of carcinomas. Members of this receptor family include EGFR (HER1), Neu (ErbB-2, HER2), ErbB-3 (HER3) and ErbB-4 (HER4), which form either homodimers or heterodimers upon ligand binding. The gene encoding ErbB-4 is expressed as a full length protein, which produces a short membrane-anchored cytoplasmic domain fragment and a long ectodomain fragment. The short fragment is heavily tyrosine phosphorylated and possesses tyrosine kinase catalytic activity toward an exogenous substrate. Proteolytic cleavage of ErbB-4 is promoted by the binding of heregulin. ErbB-4 is involved in cell proliferation and differentiation and its expression is highest in breast carcinoma cell lines, normal skeletal muscle, heart, pituitary, brain and cerebellum.