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

Vicki Waetzig1, Thomas Herdegen

  • 1Institute of Pharmacology, University Hospital Schleswig-Holstein, Hospitalstrasse 4, D-24105 Kiel, Germany. vicki.waetzig@pharmakologie.uni-kiel.de

Molecular and Cellular Neurosciences
|July 12, 2005
PubMed

Insights

Mitogen-activated protein kinase (MAPK) pathways, specifically ERK1/2 and JNK2, are vital for nerve growth factor-induced neurite regrowth after neuronal injury. This study reveals novel cross-talk between these MAPK cascades, mediated by MEKK1.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Molecular Biology

Background:

  • Peripheral neuronal cells activate signaling pathways for survival and regeneration post-injury.
  • Nerve growth factor (NGF) is a key mediator of neuronal repair processes.

Purpose of the Study:

  • To identify mitogen-activated protein kinase (MAPK) isoforms essential for NGF-induced neurite regrowth in differentiated PC12 cells after injury.
  • To elucidate the cross-talk mechanisms between MAPK pathways involved in neuronal regeneration.

Main Methods:

  • Utilized differentiated PC12 cells subjected to injury.
  • Employed MEK1 inhibitors (PD 98059, U 0126) to assess MAPK pathway activity.
  • Conducted RNA interference (RNAi) experiments to investigate pathway interactions.
  • Identified upstream kinases and their binding partners using biochemical assays.

Main Results:

  • Extracellular signal-regulated kinases 1 and 2 (ERK1/2) and c-Jun N-terminal kinase 2 (JNK2) are crucial for neurite regrowth; p38 plays no significant role.
  • MEK1 inhibitors unexpectedly blocked both ERK1/2 and JNK phosphorylation, indicating MAPK cascade cross-talk.
  • MEKK1 was identified as an upstream activator of both ERK1/2 and JNK2 pathways.
  • MEK1 and MKK7 bind competitively to MEKK1, regulating ERK1/2 and JNK2 activation.

Conclusions:

  • JNK2 and intricate MAPK pathway cross-talk are critical for neurite regeneration after neuronal injury.
  • MEKK1 acts as a central regulator, coordinating ERK1/2 and JNK2 signaling through competitive binding.
  • Findings provide new insights into the molecular mechanisms governing neuronal repair.

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