The concerted signaling of ERK1/2 and JNKs is essential for PC12 cell neuritogenesis and converges at the level of target proteins.
Mitogen-activated protein kinase (MAPK) pathways are central signaling elements, which translate and integrate stimuli from cell surface receptors into cytoplasmic and transcriptional responses. Here, we systematically compare the role of MAPKs in the nerve growth factor-induced long-term differentiation of PC12 cells and show the persistent nuclear and dose-dependent cytoplasmic activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and the increasing nuclear and cytoplasmic activation of c-Jun N-terminal kinases (JNKs). Inhibition of ERK1/2 and JNKs significantly reduced neurite outgrowth. Both synergistically controlled the expression of c-Jun, the induction and/or phosphorylation of neurofilament, and the phosphorylation of Elk-1. JNKs alone were responsible for the phosphorylation of c-Jun and activating transcription factor 2 as well as for the expression of MAPK phosphatase 1. In contrast, p38alpha was only transiently activated and marginally involved in these processes. Thus, JNKs and ERK1/2 accomplish differentiation by signaling in parallel cascades that converge only at the target level.
Waetzig
Vicki
V
Institute of Pharmacology, University Hospital Schleswig-Holstein, Hospitalstrasse 4, D-24105 Kiel, Germany.
Herdegen
Thomas
T
D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology; D002490:Central Nervous System / Q000166:cytology / Q000196:embryology / Q000201:enzymology; D004268:DNA-Binding Proteins; D004305:Dose-Response Relationship, Drug; D054638:Dual Specificity Phosphatase 1; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects / Q000378:metabolism*; D048308:Mitogen-Activated Protein Kinase 14; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D020932:Nerve Growth Factor / Q000378:metabolism / Q000494:pharmacology; D016501:Neurites / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure; D016900:Neurofilament Proteins / Q000378:metabolism; D016716:PC12 Cells; D054645:Protein Phosphatase 1; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1
D004268:DNA-Binding Proteins; C494114:Elk1 protein, rat; D004791:Enzyme Inhibitors; D016900:Neurofilament Proteins; D011518:Proto-Oncogene Proteins; D016755:Proto-Oncogene Proteins c-jun; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D020932:Nerve Growth Factor; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048308:Mitogen-Activated Protein Kinase 14; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D054645:Protein Phosphatase 1; D054638:Dual Specificity Phosphatase 1; C517021:Dusp1 protein, rat; D017027:Protein Tyrosine Phosphatases