MEKK1 controls neurite regrowth after experimental injury by balancing ERK1/2 and JNK2 signaling.
After injury, peripheral neuronal cells initiate complex signaling cascades to promote survival and regeneration. In the present study, we have identified the mitogen-activated protein kinase (MAPK) isoforms which are necessary for nerve growth factor (NGF)-induced neurite regrowth after injury of differentiated PC12 cells. Extracellular signal-regulated kinases 1 and 2 (ERK1/2) and the usually pro-apoptotic c-Jun N-terminal kinase 2 (JNK2) are crucial for neurite regrowth, while p38 plays no role in this context. Surprisingly, the MEK1 inhibitors PD 98059 and U 0126 blocked both ERK1/2 and JNK phosphorylation, indicating a novel form of balancing MAPK cascade cross-talk. Results from RNAi experiments excluded direct ERK/JNK interactions. We identified the upstream kinase MEKK1 as an activator of both the ERK1/2 and JNK2 pathways, whereby the ERK1/2 kinase MEK1 and the JNK kinase MKK7 bind to MEKK1 in a competing fashion. Our findings suggest an important role of JNK2 and MAPK pathway cross-talk in neurite regeneration.
Waetzig
Vicki
V
Institute of Pharmacology, University Hospital Schleswig-Holstein, Hospitalstrasse 4, D-24105 Kiel, Germany. vicki.waetzig@pharmakologie.uni-kiel.de
Herdegen
Thomas
T
D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D048688:MAP Kinase Kinase 7 / Q000378:metabolism; D048728:MAP Kinase Kinase Kinase 1 / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism; D020932:Nerve Growth Factor / Q000494:pharmacology; D016501:Neurites / Q000201:enzymology*; D016716:PC12 Cells; D034741:RNA, Small Interfering; D051381:Rats
D034741:RNA, Small Interfering; D020932:Nerve Growth Factor; D048056:Mitogen-Activated Protein Kinase 9; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048728:MAP Kinase Kinase Kinase 1; D048688:MAP Kinase Kinase 7