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Activation of the MAPK signal cascade by the neural cell adhesion molecule L1 requires L1 internalization

A W Schaefer1, H Kamiguchi, E V Wong

  • 1Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106-4975, USA.

The Journal of Biological Chemistry
|December 23, 1999
PubMed

Insights

The mitogen-activated protein kinase (MAPK) cascade is involved in L1-mediated axon growth. L1 internalization and signaling are coupled, regulating intracellular trafficking.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Molecular Biology

Background:

  • Axon growth is crucial for neural development and repair.
  • Intracellular signaling pathways regulate L1-mediated axon growth.
  • The precise mechanisms of L1 signaling remain unclear.

Purpose of the Study:

  • To investigate the role of the MAPK cascade in L1 signaling.
  • To elucidate the mechanisms linking L1 function to intracellular signaling.

Main Methods:

  • Co-immunoprecipitation to assess protein associations.
  • In vitro kinase assays to determine phosphorylation sites.
  • Cell-based assays in L1-expressing 3T3 cells.
  • Analysis of ERK2 activation and localization.
  • Inhibition of L1 internalization using dominant-negative dynamin.

Main Results:

  • L1 physically associates with MAPK cascade components (Raf-1, ERK2, p90(rsk)).
  • ERK2 phosphorylates L1 at conserved serines (Ser1204, Ser1248) in the cytoplasmic domain.
  • L1 cross-linking activates ERK2 in L1-expressing cells.
  • Activated ERK localizes with endocytosed L1, not cell surface L1.
  • Inhibition of L1 internalization prevents ERK activation.

Conclusions:

  • L1 signaling directly regulates L1 function through phosphorylation by ERK2.
  • L1 internalization and MAPK signaling are coupled.
  • This coupling is critical for regulating L1 intracellular trafficking.

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