title: Five carboxyl-terminal residues of neuregulin2 are critical for stimulation of signaling by the ErbB4 receptor tyrosine kinase.
abstract: The neuregulins (NRGs) are members of the epidermal growth factor (EGF) family of peptide growth factors. These hormones are agonists for the ErbB family of receptor tyrosine kinases, a family that includes the epidermal growth factor receptor (EGFR/ErbB1), ErbB2/Neu/HER2, ErbB3/HER3, and ErbB4/HER4. We recently observed that the EGF family hormone NRG2beta is a potent agonist for ErbB4. In contrast, NRG2alpha, a splicing isoform of the same gene that encodes NRG2beta, is a poor ErbB4 agonist. We hypothesized that carboxyl-terminal residues of NRG2beta are critical for stimulation of ErbB4 tyrosine phosphorylation and coupling to downstream signaling events. Here, we demonstrate that the substitution of a lysine residue for Phe45 in NRG2beta results in reduced ligand potency. We also demonstrate that substitution of a phenylalanine for Lys45 in NRG2alpha results in increased ligand potency. Finally, analyses of the gain-of-function NRG2alpha Chg5 mutant demonstrate that Gln43, Met47, Asn49, and Phe50 regulate ligand efficacy. Thus, these data indicate that carboxyl-terminal residues of NRG2beta are critical for activation of ErbB4 signaling. Moreover, these NRG2alpha and NRG2beta mutants reveal new insights into models for ligand-induced ErbB family receptor tyrosine phosphorylation and coupling to downstream signaling events.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University School of Pharmacy, West Lafayette, IN 47907-2064, USA.
authors.forename: Stuart S
authors.initials: SS
authors.lastname: Hobbs
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Cameron
authors.forename: Robert P
authors.initials: RP
authors.lastname: Hammer
authors.forename: Ann T D
authors.initials: AT
authors.lastname: Le
authors.forename: Richard M
authors.initials: RM
authors.lastname: Gallo
authors.forename: Erika N
authors.initials: EN
authors.lastname: Blommel
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: Coffing
authors.forename: Han
authors.initials: H
authors.lastname: Chang
authors.forename: David J
authors.initials: DJ
authors.lastname: Riese
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D019281:Dimerization; D066246:ErbB Receptors / Q000502:physiology*; D008969:Molecular Sequence Data; D009414:Nerve Growth Factors / Q000737:chemistry / Q000502:physiology*; D066247:Receptor, ErbB-4; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D017931:DNA Primers; C106766:NRG2 protein, human; D009414:Nerve Growth Factors; C587689:ERBB4 protein, human; D066246:ErbB Receptors; D066247:Receptor, ErbB-4