title: ErbB1 and ErbB4 generate opposing signals regulating mesenchymal cell proliferation during valvulogenesis.
abstract: Heparin-binding EGF-like growth factor (HB-EGF) plays an indispensable role in suppression of cell proliferation during mouse valvulogenesis. However, ligands of the EGF receptor (EGFR/ErbB1), including HB-EGF, are generally considered as growth-promoting factors, as shown in cancers. HB-EGF binds to and activates ErbB1 and ErbB4. We investigated the role of ErbB receptors in valvulogenesisin vivousing ErbB1- and ErbB4-deficient mice, and anex vivomodel of endocardial cushion explants. We show that HB-EGF suppresses valve mesenchymal cell proliferation through a heterodimer of ErbB1 and ErbB4, and an ErbB1 ligand (or ligands) promotes cell proliferation through a homodimer of ErbB1. Moreover, a rescue experiment with cleavable or uncleavable isoforms of ErbB4 inERBB4-null cells indicates that the cleavable JM-A, but not the uncleavable JM-B, splice variant of ErbB4 rescues the defect of the null cells. These data suggest that the cytoplasmic intracellular domain of ErbB4, rather than the membrane-anchored tyrosine kinase, achieves this suppression. Our study demonstrates that opposing signals generated by different ErbB dimer combinations function in the same cardiac cushion mesenchymal cells for proper cardiac valve formation.
authors.affiliation: Department of Cell Biology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
authors.forename: Ryo
authors.identifier: 0000-0001-5060-8100
authors.initials: R
authors.lastname: Iwamoto
authors.affiliation: Department of Cell Biology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Mine
authors.affiliation: Department of Cell Biology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Mizushima
authors.affiliation: Department of Cell Biology, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan emekada@biken.osaka-u.ac.jp.
authors.forename: Eisuke
authors.identifier: 0000-0001-8858-4781
authors.initials: E
authors.lastname: Mekada
mesh_terms: D000483:Alleles; D000818:Animals; D049109:Cell Proliferation; D004622:Embryo, Mammalian / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D005799:Genes, Dominant; D006351:Heart Valves / Q000196:embryology* / Q000378:metabolism*; D066257:Heparin-binding EGF-like Growth Factor / Q000378:metabolism; D008024:Ligands; D008648:Mesoderm / Q000166:cytology*; D018345:Mice, Knockout; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D038081:Organogenesis; D000072417:Protein Domains; D020033:Protein Isoforms / Q000378:metabolism; D066247:Receptor, ErbB-4 / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D066257:Heparin-binding EGF-like Growth Factor; D008024:Ligands; D020033:Protein Isoforms; D066246:ErbB Receptors; D066247:Receptor, ErbB-4
keywords: ErbB; HB-EGF; Mouse; Valvulogenesis