c-Jun N-terminal kinases mediate Fas-induced neurite regeneration in PC12 cells.
In response to injury, peripheral neuronal cells initiate complex signalling cascades to promote survival and regeneration. In the present study, we used a model of experimental injury in the rat pheochromocytoma cell line PC12 to investigate receptor signals that lead to neurite outgrowth. Nerve growth factor (NGF) dose-dependently induced sprouting and the expression of the NGF receptors Trk tyrosine kinase receptor (TrkA) and p75 neurotrophin receptor (p75(NTR)) as well as Fas and Fas ligand. Neurite regeneration was decreased by chemical inhibition of TrkA, but not p75(NTR), and by the Fas inhibitor protein Fas-Fc. The mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinases (JNKs) were activated in response to NGF and both significantly contributed to neurite re-growth. Interestingly, otherwise apoptotic Fas ligation supported neuronal recovery exclusively via JNKs and promoted sprouting parallel to NGF. These findings suggest a novel signal integration from the NGF and Fas pathways in the JNK axis of MAPK signalling, where JNKs function as "physiological" mediators of normally apoptotic signals.
Waetzig
Vicki
V
Institute of Pharmacology, University Hospital Schleswig-Holstein, Campus Kiel, Hospitalstrasse 4, D-24105 Kiel, Germany.
Loose
Katja
K
Haeusgen
Wiebke
W
Herdegen
Thomas
T
D000818:Animals; D015153:Blotting, Western; D004789:Enzyme Activation; D053222:Fas Ligand Protein / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D020932:Nerve Growth Factor / Q000494:pharmacology; D009416:Nerve Regeneration / Q000502:physiology*; D016501:Neurites; D016716:PC12 Cells; D051381:Rats; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D019014:fas Receptor / Q000378:metabolism / Q000502:physiology*
D053222:Fas Ligand Protein; D017475:Receptors, Nerve Growth Factor; D019014:fas Receptor; D020932:Nerve Growth Factor; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases