Ligands for ErbB-family receptors encoded by a neuregulin-like gene

Neuregulins (also called ARIA1, GGF2, heregulin3 or NDF4) are a group of polypeptide factors that arise from alternative RNA splicing of a single gene. Through their interaction with the ErbB family of receptors (ErbB2, ErbB3 and ErbB4), neuregulins help to regulate cell growth and differentiation in many tissues5–7. Here we report the cloning of a second neuregulin-like gene, neuregulin-2. The encoded product of the neuregulin-2 gene has a motif structure similar to that of neuregulins and an alternative splicing site in the epidermal growth factor(EGF)-like domain gives rise to two isoforms (α and β). Northern blot and in situ hybridization analysis of adult rat tissues indicate that expression of neuregulin-2 is highest in the cerebellum, and the expression pattern is different from that of neuregulins. Recombinant neuregulin-2β induces the tyrosine-phosphorylation of ErbB2, ErbB3 and ErbB4 in cell lines expressing all of these ErbB-family receptors. However, in cell lines with defined combinations of ErbBs, neuregulin-2βonly activates those with ErbB3 and/or ErbB4, suggesting that signalling by neuregulin-2 is mediated by ErbB3 and/or ErbB4 receptors.