MEKK1 controls neurite regrowth after experimental injury by balancing ERK1/2 and JNK2 signaling

Mol Cell Neurosci. 2005 Sep;30(1):67-78. doi: 10.1016/j.mcn.2005.06.001.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Dose-Response Relationship, Drug
  • MAP Kinase Kinase 7 / metabolism
  • MAP Kinase Kinase Kinase 1 / metabolism*
  • MAP Kinase Signaling System / physiology*
  • Mitogen-Activated Protein Kinase 1 / genetics
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3 / genetics
  • Mitogen-Activated Protein Kinase 3 / metabolism
  • Mitogen-Activated Protein Kinase 9 / metabolism
  • Nerve Growth Factor / pharmacology
  • Neurites / enzymology*
  • PC12 Cells
  • RNA, Small Interfering
  • Rats


  • RNA, Small Interfering
  • Nerve Growth Factor
  • Mitogen-Activated Protein Kinase 9
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • MAP Kinase Kinase Kinase 1
  • MAP Kinase Kinase 7