An NCAM-derived FGF-receptor agonist, the FGL-peptide, induces neurite outgrowth and neuronal survival in primary rat neurons.
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.
Neiiendam
Johanne Louise
JL
The Protein Laboratory, Institute of Molecular Pathology, University of Copenhagen, Panum Institute 6.2, Copenhagen N, Denmark. johanne@plab.ku.dk
Køhler
Lene Boding
LB
Christensen
Claus
C
Li
Shizhong
S
Pedersen
Martin Volmer
MV
Ditlevsen
Dorte Kornerup
DK
Kornum
Martin Kirkegaard
MK
Kiselyov
Vladislav V
VV
Berezin
Vladimir
V
Bock
Elisabeth
E
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D004298:Dopamine / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008636:Mesencephalon / Q000166:cytology; D019006:Neural Cell Adhesion Molecules / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D016501:Neurites / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D017468:Receptors, Fibroblast Growth Factor / Q000819:agonists* / Q000235:genetics / Q000378:metabolism
D053148:Caspase 3; D020169:Caspases; D004298:Dopamine; D019006:Neural Cell Adhesion Molecules; D010446:Peptide Fragments; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; C488618:NCAM protein (681-695), human; C494920:Akt1 protein, rat; C505407:CASP3 protein, human; C505410:Casp3 protein, rat