A peptide from the first fibronectin domain of NCAM acts as an inverse agonist and stimulates FGF receptor activation, neurite outgrowth and survival

• Published in: Journal of neurochemistry 2005-10, Vol.95 (2), p.570-583
• Main Authors: Anderson, Alexandra A., Kendal, Claire E., Garcia‐Maya, Mitla, Kenny, Anna V., Morris‐Triggs, Samantha A., Wu, Teresa, Reynolds, Richard, Hohenester, Erhard, Saffell, Jane L.
• Format: Article
• Language: English
• Subjects: 3T3 Cells; Animals; Antibodies, Blocking - pharmacology; Antimetabolites - pharmacology; bioactive peptide; Biological and medical sciences; Biotransformation - drug effects; Bromodeoxyuridine - pharmacology; Cell Proliferation - drug effects; cell survival; Cell Survival - drug effects; Cells, Cultured; Cyclization; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; fibroblast growth factor receptor; fibronectin type III domain; Fibronectins - chemistry; Fibronectins - pharmacology; Fundamental and applied biological sciences. Psychology; Isolated neuron and nerve. Neuroglia; Learning; Medical sciences; Memory; Mice; Models, Molecular; neural cell adhesion molecule; Neural Cell Adhesion Molecules - antagonists & inhibitors; Neural Cell Adhesion Molecules - immunology; Neural Cell Adhesion Molecules - metabolism; neurite outgrowth; Neurites - drug effects; Neurites - physiology; Neurology; Oligodendroglia - drug effects; Peptide Fragments - chemistry; Peptide Fragments - pharmacology; Peptides; Protein Conformation; Rats; Receptors, Fibroblast Growth Factor - agonists; Signal transduction; Vertebrates: nervous system and sense organs
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2005.03417.x

Neural cell adhesion molecule (NCAM) contributes to axon growth and guidance during development and learning and memory in adulthood. Although the Ig domains mediate homophilic binding, outgrowth activity localizes to two membrane proximal fibronectin‐like domains. The first of these contains a site identified as a potential FGF receptor (FGFR) activation motif (FRM) important for NCAM stimulation of neurite outgrowth, but its activity has hitherto remained hypothetical. Here, we have tested the effects of a domain‐specific antibody and peptides corresponding to the FRM in cellular assays in vitro. The first fibronectin domain antibody inhibited NCAM‐stimulated outgrowth, indicating the importance of the domain for NCAM function. Monomeric FRM peptide behaved as an inverse agonist; low concentrations specifically inhibited neurite outgrowth stimulated by NCAM and cellular responses to FGF2, while saturating concentrations stimulated FGFR‐dependent neurite outgrowth equivalent to NCAM itself. Dendrimeric FRM peptide was 125‐fold more active and stimulated FGFR activation, FGFR‐dependent and FGF‐mimetic neurite outgrowth and cell survival (but not proliferation). We conclude that the FRM peptide contains NCAM‐mimetic bioactivity accounted for by stimulation of FGF signalling pathways at the level of or upstream from FGF receptors, and discuss the possibility that FRM comprises part of an FGFR activation site on NCAM.