title: Nectin-1 binds and signals through the fibroblast growth factor receptor.
abstract: Nectins belong to a family of immunoglobulin (Ig)-like cell-adhesion molecules comprising four members, nectin-1 through nectin-4. Nectins are involved in formation of the mechanical adhesive puncta adherentia junctions of synapses. Nectins share the same overall structural topology with an extracellular region containing three Ig modules, a transmembrane region, and a cytoplasmic region. In nectin-1, the first and second Ig module in the extracellular region are necessary for the trans-interaction with nectin-3 and formation of cis-dimers, respectively. The function of the third Ig module of nectin-1 remains unknown. We here report the structure in solution of the third, membrane-proximal Ig module of mouse nectin-1 (nectin-1 Ig3) solved by means of nuclear magnetic resonance (NMR) spectroscopy. It belongs to the C1 set of the Ig superfamily. Nectin-1 Ig3 was produced as a recombinant protein and induced neurite outgrowth in primary cultures of hippocampal and cerebellar granule neurons, an effect abolished by treatment with the fibroblast growth factor receptor (FGFR) inhibitor SU5402, or by transfection with a dominant-negative FGFR1 construct. We showed by surface plasmon resonance (SPR) analysis that nectin-1 Ig3 directly interacted with various isoforms of FGFR. Nectin-1 Ig3 induced phosphorylation of FGFR1c in the same manner as the whole nectin-1 ectodomain, and promoted survival of cerebellar granule neurons induced to undergo apoptosis. Finally, we constructed a peptide, nectide, by employing in silico modeling of various FGFR ligand-binding sites. Nectide mimicked all the effects of nectin-1 Ig3. We suggest that FGFR is a downstream signaling partner of nectin-1.
authors.affiliation: Protein Laboratory, Department of Neuroscience and Pharmacology, Panum Institute, Blegdamsvej 3C, DK-2200 Copenhagen, Denmark.
authors.forename: Kirsten B
authors.initials: KB
authors.lastname: Bojesen
authors.forename: Ole
authors.initials: O
authors.lastname: Clausen
authors.forename: Kristian
authors.initials: K
authors.lastname: Rohde
authors.forename: Claus
authors.initials: C
authors.lastname: Christensen
authors.forename: Lanjun
authors.initials: L
authors.lastname: Zhang
authors.forename: Shizhong
authors.initials: S
authors.lastname: Li
authors.forename: Lene
authors.initials: L
authors.lastname: Køhler
authors.forename: Steen
authors.initials: S
authors.lastname: Nielbo
authors.forename: Janne
authors.initials: J
authors.lastname: Nielsen
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Gjørlund
authors.forename: Flemming M
authors.initials: FM
authors.lastname: Poulsen
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Bock
authors.forename: Vladimir
authors.initials: V
authors.lastname: Berezin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D002470:Cell Survival; D018360:Crystallography, X-Ray; D016222:Fibroblast Growth Factor 2 / Q000502:physiology; D057809:HEK293 Cells; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D000075983:Nectins; D016501:Neurites / Q000378:metabolism / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000502:physiology; D010766:Phosphorylation; D061251:Primary Cell Culture; D011485:Protein Binding; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D051381:Rats; D017208:Rats, Wistar; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000737:chemistry / Q000378:metabolism*; D017479:Receptors, Platelet-Derived Growth Factor / Q000737:chemistry; D015398:Signal Transduction; D020349:Surface Plasmon Resonance
chemical_list: D015815:Cell Adhesion Molecules; C000619010:NECTIN1 protein, human; C000619014:NECTIN3 protein, human; C000619015:Nectin1 protein, mouse; C000619017:Nectin3 protein, mouse; D000075983:Nectins; D020033:Protein Isoforms; D016222:Fibroblast Growth Factor 2; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017479:Receptors, Platelet-Derived Growth Factor