Cdk5, which is essential for CNS development, depends on its association with
p35 (or truncated p25) or p39, but the regulatory mechanisms whereby Cdk5 is
activated have not yet been fully elucidated. Studies on PC12 cells showed that
Cdk5/p25 activity is modulated by an unidentified kinase
that phosphorylates Cdk5 at Ser159 and enhances its kinase activity (Sharma et al., 1999 PNAS USA 96,11156). In this study, we have partially purified a bovine
brain enzyme that can phosphorylate the Cdk5(149-163) peptide but not the Cdk5(149-163)A159 peptide.
The enzyme, which contains Cdk7, cyclin H, and Mat1,
specifically phosphorylates Ser159 of Cdk5(149-163) and enhances Cdk5/p25 activity. The active
Cdk7-containing enzyme also phosphorylates and
activates wt Cdk5 but not mutated Cdk5(Ser159Ala).
Likewise, Cdk7 or cyclin H immunoprecipitate
from mouse brain specifically phosphorylates wt Cdk5
at Ser159 and enhances Cdk5/p25 activity. Conversely, blocked Cdk7 immunoprecipitate does not phosphorylate
nor activate Cdk5. In addition, the Cdk7 substrate, CTD of RNAPII, causes a
dose-dependent decline in Cdk5 activation by Cdk7. These findings indicate that
Cdk7 functions as a Cdk5 activating kinase in brain.
Indeed, elevated Cdk5 activity in the developing E18 mouse brain coincides with
increased Cdk7 kinase activity. Copyright 2003 S. Karger AG,