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Site-specific dephosphorylation of doublecortin (DCX) by protein phosphatase 1 (PP1)

Anat Shmueli1, Amos Gdalyahu, Sivan Sapoznik

  • 1Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.

Molecular and Cellular Neurosciences
|March 15, 2006
PubMed

Insights

Neurabin II and phosphatase PP1 dephosphorylate doublecortin (DCX), a protein crucial for neuronal migration. This regulation is vital for preventing brain malformations like lissencephaly.

Area of Science:

  • Neuroscience
  • Cell Biology
  • Developmental Biology

Background:

  • Mutations in doublecortin (DCX) are linked to human brain malformations, including X-linked lissencephaly and double cortex syndrome.
  • Doublecortin (DCX) is a key protein involved in neuronal migration during cortical development and is known to be highly phosphorylated in these cells.

Purpose of the Study:

  • To investigate the mechanisms regulating the phosphorylation state of doublecortin (DCX) during neuronal migration.
  • To identify the specific phosphatases involved in DCX dephosphorylation and their interaction partners.

Main Methods:

  • In vitro biochemical assays to study DCX dephosphorylation by phosphatase PP1.
  • Co-immunoprecipitation and overexpression studies to analyze the interaction between DCX, Neurabin II, and PP1.
  • Analysis of protein expression patterns during cortical development.

Main Results:

  • Dephosphorylation of specific JNK-phosphorylated sites on DCX is mediated by Neurabin II, which recruits the phosphatase PP1.
  • While PP1 expression is widespread, DCX and Neurabin II show dynamic expression and are coexpressed in migrating neurons.
  • In vitro studies confirmed site-specific dephosphorylation of DCX by PP1, dependent on an intact RVXF motif, and this process can be enhanced by Neurabin II.

Conclusions:

  • Neurabin II and PP1 play a critical role in the dephosphorylation of DCX, regulating its function during neuronal migration.
  • The dynamic recruitment of DCX to scaffold proteins like JIP-1/2 for phosphorylation and Neurabin II for dephosphorylation is essential for normal neuronal migration.
  • Dysregulation of this phosphorylation/dephosphorylation balance may contribute to the pathogenesis of lissencephaly and related disorders.

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