ErbB4 and its isoforms - Selective regulation of growth factor responses by naturally occurring receptor variants

ErbB4 is a member of the epidermal growth factor receptor (EGFR, ErbB) fami ly that mediates responses to neuregulins and other EGF-like growth factors . ErbB4 is a central regulator of cardiovascular and neural development as well as differentiation of the mammary gland. A role for ErbB4 has also bee n implicated in malignancies and heart diseases. Four structurally and func tionally distinct ErbB4 isoforms have recently been identified. One pair of isoforms differs within their extracellular juxtamembrane domains. These j uxtamembrane ErbB4 isoforms are either susceptible or resistant to proteoly tic processing that release a soluble receptor ectodomain. Another pair of ErbB4 isoforms differs within their cytoplasmic tails. Analysis of the intr acellular signal transduction pathways indicates that both cytoplasmic ErbB 4 isoforms can couple to the Shc-MAPK signaling pathway, while the other on e is incapable of coupling to the phosphoinositide 3-kinase (PI3-K)-Akt pat hway. The differences in the activation of signaling cascades are reflected in the cellular responses stimulated via the cytoplasmic isoforms. Both cy toplasmic ErbB4 isoforms can stimulate proliferation, but the isoform that cannot activate PI3-K is defective in stimulating cellular survival and che motaxis. Together these four naturally occurring receptor variants provide a new level of diversity to the control of growth factor-stimulated cellula r responses. Thus, the ErbB4 isoforms may have distinct and specific roles in the regulation of various developmental and pathological processes. (Tre nds Cardiovasc Med 10;2000:304-310). (C) 2001, Elsevier Science Inc.