Analysis of non-canonical fibroblast growth factor receptor 1 (FGFR1) interaction reveals regulatory and activating domains of neurofascin.
Fibroblast growth factor receptors (FGFRs) are important for many different mechanisms, including cell migration, proliferation, differentiation, and survival. Here, we show a new link between FGFR1 and the cell adhesion molecule neurofascin, which is important for neurite outgrowth. After overexpression in HEK293 cells, embryonal neurofascin isoform NF166 was able to associate with FGFR1, whereas the adult isoform NF186, differing from NF166 in additional extracellular sequences, was deficient. Pharmacological inhibitors and overexpression of dominant negative components of the FGFR signaling pathway pointed to the activation of FGFR1 after association with neurofascin in neurite outgrowth assays in chick tectal neurons and rat PC12-E2 cells. Both extra- and intracellular domains of embryonal neurofascin isoform NF166 were able to form complexes with FGFR1 independently. However, the cytosolic domain was both necessary and sufficient for the activation of FGFR1. Cytosolic serine residues 56 and 100 were shown to be essential for the neurite outgrowth-promoting activity of neurofascin, whereas both amino acid residues were dispensable for FGFR1 association. In conclusion, the data suggest a neurofascin intracellular domain, which activates FGFR1 for neurite outgrowth, whereas the extracellular domain functions as an additional, regulatory FGFR1 interaction domain in the course of development.
Kirschbaum
Katja
K
Department of Molecular Biology, Naturwissenschaftliches und Medizinisches Institut an der Universität Tübingen, Markwiesenstrasse 55, 72770 Reutlingen, Germany
Kriebel
Martin
M
Kranz
Eva Ursula
EU
Pötz
Oliver
O
Volkmer
Hansjürgen
H
D000818:Animals; D015815:Cell Adhesion Molecules / Q000737:chemistry*; D002460:Cell Line; D002642:Chick Embryo; D003600:Cytosol / Q000378:metabolism; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009414:Nerve Growth Factors / Q000737:chemistry*; D016501:Neurites / Q000378:metabolism; D016716:PC12 Cells; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism*
D015815:Cell Adhesion Molecules; C054305:NFASC protein, human; D009414:Nerve Growth Factors; C504595:Nfasc protein, Gallus gallus; C504593:Nfasc protein, mouse; C504594:Nfasc protein, rat; D051496:Receptor, Fibroblast Growth Factor, Type 1