Neuregulin-3 (NRG3): A novel neural tissue-enriched protein that binds and activates ErbB4

Neuregulin-3 (NRG3): A novel neural tissue-enriched protein that binds and activates ErbB4

^*Departments of Molecular Biology, ^†Protein Chemistry, and ^‡Pathology, Genentech, Inc., South San Francisco, CA 94080

Communicated by David V. Goeddel, Tularik, Inc., South San Francisco, CA (received for review March 27, 1997)

Abstract

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.

Footnotes

↵ § To whom reprint requests should be addressed at: Department of Molecular Biology, Mailstop 37, Genentech, Inc., 460 Point San Bruno Boulevard, South San Francisco, CA 94080. e-mail: ski{at}gene.com.
Abbreviations: EGF, epidermal growth factor; EGFR, EGF receptor; NRG3, Neuregulin-3; NRG1, Neuregulin-1; SMDF, sensory and motor neuron-derived factor; FACS, fluorescence-activated cell sorter; E, embryonic day.