Developmental regulation of the proteolysis of the p35 cyclin-dependent kinase 5 activator by phosphorylation.
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.
Saito
Taro
T
Department of Biological Sciences, Graduate School of Science, Tokyo Metropolitan University, Minami-Osawa, Hachiohji, Tokyo 192-0397, Japan. tasaito@comp.metro-u.ac.jp
Onuki
Reiko
R
Fujita
Yuichi
Y
Kusakawa
Gen-ichi
G
Ishiguro
Koichi
K
Bibb
James A
JA
Kishimoto
Takeo
T
Hisanaga
Shin-ichi
S
D000367:Age Factors; D000818:Animals; D001921:Brain / Q000196:embryology* / Q000254:growth & development / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; D051381:Rats
D009097:Multienzyme Complexes; D009419:Nerve Tissue Proteins; C089495:neuronal Cdk5 activator (p25-p35); D051360:Cyclin-Dependent Kinase 5; C495907:Cdk5 protein, rat; D018844:Cyclin-Dependent Kinases; D002154:Calpain; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex