Calpastatin, an endogenous calpain-inhibitor protein, regulates the cleavage of the Cdk5 activator p35 to p25

Ko Sato, Seiji Minegishi, Jiro Takano, Florian Plattner, Taro Saito, Akiko Asada, Hiroyuki Kawahara, Nobuhisa Iwata, Takaomi C. Saido, Shin Ichi Hisanaga

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Cyclin-dependent kinase 5 (Cdk5) is a Ser/Thr kinase that is activated by binding to its regulatory subunit, p35. The calpain-mediated cleavage of p35 to p25 and the resulting aberrant activity and neurotoxicity of Cdk5 have been implicated in neurological disorders, such as Alzheimer's disease. To gain further insight into the molecular mechanisms underlying the pathological function of Cdk5, we investigated the role of the calpain inhibitor protein calpastatin (CAST), in controlling the aberrant production of p25. For this purpose, brain tissue from wild-type, CAST-over-expressing (transgenic), and CAST knockout mice were analyzed. Cleavage of p35 to p25 was increased in extracts from CAST knockout mice, compared with wild-type. Conversely, generation of p25 was not detected in brain lysates from CAST-over-expressing mice. CAST expression was 5-fold higher in mouse cerebellum than cerebral cortex. Accordingly, p25 production was lower in the cerebellum than the cerebral cortex. Furthermore, the Ca2+-dependent degradation of p35 by proteasome was evident when calpain was inhibited. Taken together, these results suggest that CAST is a crucial regulator of calpain activity, the production of p25, and, hence, the deregulation of Cdk5. Therefore, impairment of CAST expression and its associated mechanisms may contribute to the pathogenesis of neurodegenerative disorders.

Original languageEnglish (US)
Pages (from-to)504-515
Number of pages12
JournalJournal of Neurochemistry
Volume117
Issue number3
DOIs
StatePublished - May 1 2011

Keywords

  • Alzheimer's disease
  • calpain
  • calpastatin
  • cyclin-dependent kinase 5

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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    Sato, K., Minegishi, S., Takano, J., Plattner, F., Saito, T., Asada, A., Kawahara, H., Iwata, N., Saido, T. C., & Hisanaga, S. I. (2011). Calpastatin, an endogenous calpain-inhibitor protein, regulates the cleavage of the Cdk5 activator p35 to p25. Journal of Neurochemistry, 117(3), 504-515. https://doi.org/10.1111/j.1471-4159.2011.07222.x