Abstract
The mechanism of fibroblast growth factor receptor (FGFR) activation by the neural cell adhesion molecule (NCAM) is not well understood. A motif in the second NCAM fibronectin type III (FN3) module, termed FGL, has by means of nuclear magnetic resonance (NMR) and surface plasmon resonance (SPR) analyses been demonstrated to be involved in NCAM–FGFR interactions. An FGFR activation motif (FRM) in the first NCAM FN3 module also has been suggested to take part in NCAM interactions with FGFR. Here, we show for the first time that a peptide motif in the second NCAM FN3 module, different from the previously described FGL motif (NLIKQDDGGSPIRHY; termed BCL) binds and activates FGFR and induces FGFR-dependent neurite outgrowth in cultures of cerebellar granule neurons. Our results provide evidence that the BCL motif is one of the multiple FGFR binding sites in NCAM.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Ronn LC, Doherty P, Holm A et al (2000) Neurite outgrowth induced by a synthetic peptide ligand of neural cell adhesion molecule requires fibroblast growth factor receptor activation. J Neurochem 75:665–671
Walmod PS, Kolkova K, Berezin V et al (2004) Zippers make signals: NCAM-mediated molecular interactions and signal transduction. Neurochem Res 29:2015–2035
Kiselyov VV, Soroka V, Berezin V et al (2005) Structural biology of NCAM homophilic binding and activation of FGFR. J Neurochem 94:1169–1179
Ditlevsen DK, Povlsen GK, Berezin V et al (2008) NCAM-induced intracellular signaling revisited. J Neurosci Res 86:727–743
Kiselyov VV, Skladchikova G, Hinsby AM et al (2003) Structural basis for a direct interaction between FGFR1 and NCAM and evidence for a regulatory role of ATP. Structure 11:691–701
Neiiendam JL, Kohler LB, Christensen C et al (2004) An NCAM-derived FGF-receptor agonist, the FGL-peptide, induces neurite outgrowth and neuronal survival in primary rat neurons. J Neurochem 91:920–935
Cambon K, Hansen SM, Venero C et al (2004) A synthetic neural cell adhesion molecule mimetic peptide promotes synaptogenesis, enhances presynaptic function, and facilitates memory consolidation. J Neurosci 24:4197–4204
Skibo GG, Lushnikova IV, Voronin KY et al (2005) A synthetic NCAM-derived peptide, FGL, protects hippocampal neurons from ischemic insult both in vitro and in vivo. Eur J Neurosci 22:1589–1596
Secher T, Novitskaia V, Berezin V et al (2006) A neural cell adhesion molecule-derived fibroblast growth factor receptor agonist, the FGL-peptide, promotes early postnatal sensorimotor development and enhances social memory retention. Neuroscience 141:1289–1299
Klementiev B, Novikova T, Novitskaya V et al (2007) A neural cell adhesion molecule-derived peptide reduces neuropathological signs and cognitive impairment induced by Abeta25–35. Neuroscience 145:209–224
Anderson AA, Kendal CE, Garcia-Maya M et al (2005) A peptide from the first fibronectin domain of NCAM acts as an inverse agonist and stimulates FGF receptor activation, neurite outgrowth and survival. J Neurochem 95:570–583
Carafoli F, Saffell JL, Hohenester E (2008) Structure of the tandem fibronectin type 3 domains of neural cell adhesion molecule. J Mol Biol 377:524–534
Ronn LC, Ralets I, Hartz BP et al (2000) A simple procedure for quantification of neurite outgrowth based on stereological principles. J Neurosci Methods 100:25–32
Kohler LB, Berezin V, Bock E et al (2003) The role of metallothionein II in neuronal differentiation and survival. Brain Res 992:128–136
Kiryushko D, Kofoed T, Skladchikova G et al (2003) A synthetic peptide ligand of neural cell adhesion molecule (NCAM), C3d, promotes neuritogenesis and synaptogenesis and modulates presynaptic function in primary cultures of rat hippocampal neurons. J Biol Chem 278:12325–12334
Mendiratta SS, Sekulic N, Hernandez-Guzman FG et al (2006) A novel alpha-helix in the first fibronectin type III repeat of the neural cell adhesion molecule is critical for N-glycan polysialylation. J Biol Chem 281:36052–36059
Soroka V, Kolkova K, Kastrup JS et al (2003) Structure and interactions of NCAM Ig1-2-3 suggest a novel zipper mechanism for homophilic adhesion. Structure 11:1291–1301
Furdui CM, Lew ED, Schlessinger J et al (2006) Autophosphorylation of FGFR1 kinase is mediated by a sequential and precisely ordered reaction. Mol Cell 21:711–717
Garcia-Maya M, Anderson AA, Kendal CE et al (2006) Ligand concentration is a driver of divergent signaling and pleiotropic cellular responses to FGF. J Cell Physiol 206:386–393
Bell CA, Tynan JA, Hart KC et al (2000) Rotational coupling of the transmembrane and kinase domains of the Neu receptor tyrosine kinase. Mol Biol Cell 11:3589–3599
Li S, Christensen C, Kiselyov VV et al (2008) Fibroblast growth factor-derived peptides: functional agonists of the fibroblast growth factor receptor. J Neurochem 104:667–682
Acknowledgements
Research was financially supported by grants from the Danish Medical and Natural Science Research Councils, the Lundbeck Foundation, and the European Union-supported integrated project PROMEMORIA (FP6 frame program-integrated project PROMEMORIA-LSHM-CT-2005-512012).
Author information
Authors and Affiliations
Corresponding author
Additional information
Special issue article in honor of Dr. Anna Maria Giuffrida-Stella.
Rights and permissions
About this article
Cite this article
Jacobsen, J., Kiselyov, V., Bock, E. et al. A Peptide Motif from the Second Fibronectin Module of the Neural Cell Adhesion Molecule, NCAM, NLIKQDDGGSPIRHY, is a Binding Site for the FGF Receptor. Neurochem Res 33, 2532–2539 (2008). https://doi.org/10.1007/s11064-008-9680-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11064-008-9680-2