Neuregulin-3 (NRG3): A Novel Neural Tissue-Enriched Protein that Binds and Activates ErbB4

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 94; no. 18; pp. 9562 - 9567
• Main Authors: Zhang, Dongxiao, Sliwkowski, Mark X., Mark, Melanie, Frantz, Gretchen, Akita, Robert, Sun, Yang, Hillan, Kenneth, Crowley, Craig, Brush, Jennifer, Godowski, Paul J.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 02.09.1997; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences of the USA
• Subjects: Amino Acid Sequence; Amino acids; Animals; Antibodies; Biochemistry; Biological Sciences; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Line; Cell lines; Cloning, Molecular; Complementary DNA; Enzyme Activation; ErbB Receptors - genetics; ErbB Receptors - metabolism; Gene Expression Regulation, Developmental; Humans; Intracellular Signaling Peptides and Proteins; K562 cells; Ligands; Mice; Molecular Sequence Data; Nerve Growth Factors - genetics; Nerve Growth Factors - metabolism; Neuregulins; Neurons; Organ Specificity; Phosphorylation; Proteins; Receptor, ErbB-4; Receptors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.94.18.9562

We describe the identification of Neuregulin-3 (NRG3), a novel protein that is structurally related to the neuregulins (NRG1). The NRG1/neuregulins are a diverse family of proteins that arise by alternative splicing from a single gene. These proteins play an important role in controlling the growth and differentiation of glial, epithelial, and muscle cells. The biological effects of NRG1 are mediated by receptor tyrosine kinases ErbB2, ErbB3, and ErbB4. However, genetic studies have suggested that the activity of ErbB4 may also be regulated in the central nervous system by a ligand distinct from NRG1. NRG3 is predicted to contain an extracellular domain with an epidermal growth factor (EGF) motif, a transmembrane domain, and a large cytoplasmic domain. We show that the EGF-like domain of NRG3 binds to the extracellular domain of ErbB4 in vitro. Moreover, NRG3 binds to ErbB4 expressed on cells and stimulates tyrosine phosphorylation of this receptor. The expression of NRG3 is highly restricted to the developing and adult nervous system. These data suggest that NRG3 is a novel, neural-enriched ligand for ErbB4.