Developmental regulation of the proteolysis of the p35 cyclin-dependent kinase 5 activator by phosphorylation

Taro Saito, Reiko Onuki, Yuichi Fujita, Gen ichi Kusakawa, Koichi Ishiguro, James A. Bibb, Takeo Kishimoto, Shin ichi Hisanaga

Research output: Contribution to journalArticle

80 Scopus citations

Abstract

Cyclin-dependent kinase 5 (Cdk5), a cdc2-related kinase expressed in postmitotic neurons, is activated by association with a brain-specific activator, p35. It has been suggested that the conversion of p35 to p25 by the protease calpain is involved in neuronal cell death. However, p35 protein is turned over rapidly via proteasomal degradation in living neurons. In this study we show that the phosphorylation of p35 by Cdk5 suppresses the cleavage to p25 by calpain, whereas phosphorylation facilitates the proteasomal degradation of p35. The phosphorylation site in p35 that might be involved in preventing calpain cleavage was distinct from the phosphorylation site involved in facilitating proteasomal degradation. A phosphorylated form of p35 that was resistant to cleavage by calpain was more prevalent in the fetal brain, whereas the unphosphorylated form of p35 occurred in the adult brain. These results suggest that the phosphorylation of p35 serves as a protective mechanism that suppresses the generation of p25 in developing brains.

Original languageEnglish (US)
Pages (from-to)1189-1197
Number of pages9
JournalJournal of Neuroscience
Volume23
Issue number4
DOIs
StatePublished - Feb 15 2003

Keywords

  • Calpain
  • Cdk5
  • Cell death
  • Development
  • Neuron
  • Proteasome
  • Protein kinase

ASJC Scopus subject areas

  • Neuroscience(all)

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