Promotion of neurite outgrowth by fibroblast growth factor receptor 1 overexpression and lysosomal inhibition of receptor degradation in pheochromocytoma cells and adult sensory neurons.
Basic fibroblast growth factor (FGF-2) is up-regulated in response to a nerve lesion and promotes axonal regeneration by activation of the tyrosine kinase receptor fibroblast growth factor receptor 1 (FGFR1). To determine the effects of elevated FGFR1 levels on neurite outgrowth, overexpression was combined with lysosomal inhibition of receptor degradation. In pheochromocytoma (PC12) cells, FGFR1 overexpression resulted in flattened morphology, increased neurite outgrowth and activation of extracellular signal-regulated kinase (ERK) and AKT. Degradation of FGFR1 was inhibited by the lysosomal inhibitor leupeptin and by the proteasomal inhibitor lactacystin. In rat primary adult neurons, FGFR1 overexpression enhanced FGF-2-induced axon growth which was further increased by co-treatment with leupeptin. Lysosomal inhibition of receptor degradation concomitant with ligand stimulation of neurons overexpressing FGFR1 provides new insight in tyrosine kinase receptor-mediated promotion of axon regeneration and demonstrates that adult sensory neurons express sub-optimal levels of tyrosine kinase receptors for neurotrophic factors.
Hausott
B
B
Division of Neuroanatomy, Innsbruck Medical University, Muellerstrasse 59, Innsbruck, Austria.
Schlick
B
B
Vallant
N
N
Dorn
R
R
Klimaschewski
L
L
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D015153:Blotting, Western; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000737:chemistry; D007976:Leupeptins / Q000494:pharmacology; D008024:Ligands; D008247:Lysosomes / Q000187:drug effects / Q000502:physiology*; D016501:Neurites / Q000502:physiology*; D016716:PC12 Cells; D010673:Pheochromocytoma / Q000378:metabolism*; D051381:Rats; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D011984:Sensory Receptor Cells / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D008024:Ligands; C067713:lactacystin; D049452:Green Fluorescent Proteins; D005346:Fibroblast Growth Factors; D051496:Receptor, Fibroblast Growth Factor, Type 1; C032854:leupeptin; D000111:Acetylcysteine