An NCAM-derived FGF-receptor agonist, the FGL-peptide, induces neurite outgrowth and neuronal survival in primary rat neurons

Authors

  • Johanne Louise Neiiendam,

    1. The Protein Laboratory, Institute of Molecular Pathology, University of Copenhagen, Panum Institute 6.2, Copenhagen N, Denmark
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  • Lene Boding Køhler,

    1. ENKAM Pharmaceuticals A/S, Copenhagen Ø, Denmark
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  • Claus Christensen,

    1. The Protein Laboratory, Institute of Molecular Pathology, University of Copenhagen, Panum Institute 6.2, Copenhagen N, Denmark
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  • Shizhong Li,

    1. The Protein Laboratory, Institute of Molecular Pathology, University of Copenhagen, Panum Institute 6.2, Copenhagen N, Denmark
    2. ENKAM Pharmaceuticals A/S, Copenhagen Ø, Denmark
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  • Martin Volmer Pedersen,

    1. The Protein Laboratory, Institute of Molecular Pathology, University of Copenhagen, Panum Institute 6.2, Copenhagen N, Denmark
    2. ENKAM Pharmaceuticals A/S, Copenhagen Ø, Denmark
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  • Dorte Kornerup Ditlevsen,

    1. The Protein Laboratory, Institute of Molecular Pathology, University of Copenhagen, Panum Institute 6.2, Copenhagen N, Denmark
    2. ENKAM Pharmaceuticals A/S, Copenhagen Ø, Denmark
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  • Martin Kirkegaard Kornum,

    1. The Protein Laboratory, Institute of Molecular Pathology, University of Copenhagen, Panum Institute 6.2, Copenhagen N, Denmark
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  • Vladislav V. Kiselyov,

    1. The Protein Laboratory, Institute of Molecular Pathology, University of Copenhagen, Panum Institute 6.2, Copenhagen N, Denmark
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  • Vladimir Berezin,

    1. The Protein Laboratory, Institute of Molecular Pathology, University of Copenhagen, Panum Institute 6.2, Copenhagen N, Denmark
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  • Elisabeth Bock

    1. The Protein Laboratory, Institute of Molecular Pathology, University of Copenhagen, Panum Institute 6.2, Copenhagen N, Denmark
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Address correspondence and reprint requests to Johanne Neiiendam, Protein Laboratory, Institute of Molecular Pathology, University of Copenhagen, Panum Institute 6.2.46, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark. E-mail: johanne@plab.ku.dk

Abstract

The Neural Cell Adhesion Molecule (NCAM) plays a crucial role in development of the central nervous system regulating cell migration, differentiation and synaptogenesis. NCAM mediates cell–cell adhesion through homophilic NCAM binding, subsequently resulting in activation of the fibroblast growth factor receptor (FGFR). NCAM-mediated adhesion leads to activation of various intracellular signal transduction pathways, including the Ras-mitogen activated protein kinase (MAPK) and the phosphatidylinositol-3-kinase (PI3K)-Akt pathways. A synthetic peptide derived from the second fibronectin type III module of NCAM, the FGL peptide, binds to and induces phosphorylation of FGFR without prior homophilic NCAM binding. We here present evidence that this peptide is able to mimic NCAM heterophilic binding to the FGFR by inducing neuronal differentiation as reflected by neurite outgrowth through a direct interaction with FGFR in primary cultures of three different neuronal cell types all expressing FGFR subtype 1: dopaminergic, hippocampal and cerebellar granule neurons. Moreover, we show that the FGL peptide promotes neuronal survival upon induction of cell death in the same three cell types. The effects of the FGL peptide are shown to depend on activation of FGFR and the MAPK and PI3K intracellular signalling pathways, all three kinases being necessary for the effects of FGL on neurite outgrowth and neuronal survival.

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