title: Neuregulin-3 (NRG3): a novel neural tissue-enriched protein that binds and activates ErbB4.
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.
authors.affiliation: Department of Molecular Biology, Genentech, Inc., South San Francisco, CA 94080, USA.
authors.forename: D
authors.initials: D
authors.lastname: Zhang
authors.forename: M X
authors.initials: MX
authors.lastname: Sliwkowski
authors.forename: M
authors.initials: M
authors.lastname: Mark
authors.forename: G
authors.initials: G
authors.lastname: Frantz
authors.forename: R
authors.initials: R
authors.lastname: Akita
authors.forename: Y
authors.initials: Y
authors.lastname: Sun
authors.forename: K
authors.initials: K
authors.lastname: Hillan
authors.forename: C
authors.initials: C
authors.lastname: Crowley
authors.forename: J
authors.initials: J
authors.lastname: Brush
authors.forename: P J
authors.initials: PJ
authors.lastname: Godowski
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D003001:Cloning, Molecular; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D051379:Mice; D008969:Molecular Sequence Data; D009414:Nerve Growth Factors / Q000235:genetics* / Q000378:metabolism; D020880:Neuregulins; D009928:Organ Specificity; D066247:Receptor, ErbB-4
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; C486357:NRG3 protein, human; D009414:Nerve Growth Factors; D020880:Neuregulins; C108113:Nrg3 protein, mouse; C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4