Neuroplastin‐55 binds to and signals through the fibroblast growth factor receptor

Abstract

Neuroplastin (Np) is a glycoprotein belonging to the immunoglobulin superfamily of cell adhesion molecules (CAMs) and existing in two isoforms, Np55 and Np65, named according to their molecular weights. The extracellular part of Np65 contains three immunoglobulin (Ig)-like modules (Ig1, Ig2, and Ig3), whereas Np55 lacks the Ig1 module. Of these two isoforms, only Np65 is involved in homophilic interactions resulting in cell adhesion, whereas the role of Np55 is poorly understood. The present study reports for the first time the crystal structure of the ectodomain of Np55 at 1.95-A resolution and demonstrates that Np55 binds to and activates the fibroblast growth factor receptor 1 (FGFR1). Furthermore, we identify a sequence motif in the Ig2 module of Np55 interacting with FGFR1 and show that a synthetic peptide encompassing this motif, termed narpin, binds to and activates FGFR1. We show that both Np55 and the narpin peptide induce neurite outgrowth through FGFR1 activation and that Np55 increases synaptic calcium concentration in an FGFR1-dependent manner. Moreover, we demonstrate that narpin has an antidepressive-like effect in rats subjected to the forced swim test, suggesting that Np55-induced signaling may be involved in synaptic plasticity in vivo. Owczarek, S., Kiryushko, D., Larsen, M. H., Kastrup, J. S., Gajhede, M., Sandi, C., Berezin, V., Bock, E., Soroka, V. Neuroplastin-55 binds to and signals through the fibroblast growth factor receptor.

Asbestos‐associated genome‐wide DNA methylation changes in lung cancer

“…27 Although the role of NPTN (neuroplastin) [particularly the short isoform] remains unclear, it has been postulated to be involved in modulating intracellular Ca 21 as a result of its interaction with FGFR. 28 Stimulation of a Ca 21 sensing receptor has been shown to promote the expression of TRPC3, a member of the canonical transient receptor potential channels, leading to perturbation in Ca 21 homeostasis. 29 We found TRPC3 methylation variation prominent in lung cancer from cases without asbestos exposure, whereas in tumors of the asbestos-exposed, TRPC3 methylation remained at the same level as in peripheral lung tissue.…”

Nectin-1 Binds and Signals through the Fibroblast Growth Factor Receptor

“…The Third Ig Module of Nectin-1 Induces Neurite Outgrowth in an FGFR Activation-dependent Manner-Several other neuronal CAMs, such as L1, NCAM, N-cadherin, neuroplastin, and neurofascin, are able to induce neuronal differentiation, reflected by neurite outgrowth, in immature neurons (19,34,35). We investigated whether nectin-1 Ig3 also has neuritogenic properties.…”

“…In CGNs, the response was lower but still statistically significant and reached a plateau with a maximal response of 140 Ϯ 10% at a concentration of 0.47 M nectin-1 Ig3. The neuritogenic effect of various CAMs is at least partially dependent on FGFR activation (19,34,35). Therefore, we inhibited FGFR in CGNs to investigate the involvement of FGFR activation in nectin-1 Ig3-induced neurite outgrowth.…”

“…Numerous CAMs such as NCAM, L1, N-cadherin, neurofascin, and neuroplastin (19,34,35), which all signal through the activation of FGFR, also display neuritogenic properties. All of these CAMs have fairly different downstream signaling mechanisms that involve their specific cytoplasmic domains.…”

“…Furthermore, we hypothesized that nectin-1 Ig3 mediates its neuritogenic effects through the fibroblast growth factor receptors (FGFRs), because the FGFRs play critical roles during development of CNS, and has been shown to interact directly with other neuronal CAMs (16 -19). The FGFR1-3 are, among other regions, expressed in the cerebellum and hippocampus (19) overlapping the expression pattern of nectin-1 in the CNS. We expressed the third Ig module of nectin-1 as a recombinant protein in the Pichia pastoris expression system and used nuclear magnetic resonance (NMR) spectroscopy to solve its structure in solution.…”