Cosignaling of NCAM via lipid rafts and the FGF receptor is required for neuritogenesis.
The neural cell adhesion molecule (NCAM) has been reported to stimulate neuritogenesis either via nonreceptor tyrosine kinases or fibroblast growth factor (FGF) receptor. Here we show that lipid raft association of NCAM is crucial for activation of the nonreceptor tyrosine kinase pathway and induction of neurite outgrowth. Transfection of hippocampal neurons of NCAM-deficient mice revealed that of the three major NCAM isoforms only NCAM140 can act as a homophilic receptor that induces neurite outgrowth. Disruption of NCAM140 raft association either by mutation of NCAM140 palmitoylation sites or by lipid raft destruction attenuates activation of the tyrosine focal adhesion kinase and extracellular signal-regulated kinase 1/2, completely blocking neurite outgrowth. Likewise, NCAM-triggered neurite outgrowth is also completely blocked by a specific FGF receptor inhibitor, indicating that cosignaling via raft-associated kinases and FGF receptor is essential for neuritogenesis.
Niethammer
Philipp
P
Zentrum für Molekulare Neurobiologie, Universität Hamburg, D-20246 Hamburg, Germany.
Delling
Markus
M
Sytnyk
Vladimir
V
Dityatev
Alexander
A
Fukami
Kiyoko
K
Schachner
Melitta
M
D000818:Animals; D016466:CHO Cells; D002455:Cell Division; D006224:Cricetinae; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006624:Hippocampus / Q000166:cytology; D021962:Membrane Microdomains / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D019006:Neural Cell Adhesion Molecules / Q000502:physiology*; D016501:Neurites / Q000502:physiology*; D019308:Palmitic Acid / Q000378:metabolism; D020033:Protein Isoforms / Q000502:physiology; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D017468:Receptors, Fibroblast Growth Factor / Q000502:physiology*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured
D019006:Neural Cell Adhesion Molecules; D020033:Protein Isoforms; D017468:Receptors, Fibroblast Growth Factor; D019308:Palmitic Acid; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496051:Ptk2 protein, mouse; C496052:Ptk2 protein, rat