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Fig. 11.2 Regulation of CDK-cyclin activity by phosphorylation. Phosphorylation of CDK on
T14 and Y15 by the Wee1 and Myt1 kinases keeps the complex inactive. Dephosphorylation of
these two residues by the CDC25 phosphatases activates the complex. Phosphorylation of one
further residue, T161 within the activation loop of CDK is required for full activation of the
complex.
Once
activated,
CDK-cyclins
can
phosphorylate
and
activate
their
downstream
substrates
Successive oscillations of cyclin levels throughout cell division control the
overall activity of a given CDK-cyclin complex during each cell cycle phase.
Cyclin protein levels are regulated by a balance between gene expression and
protein degradation. Cyclin E for example, is expressed during a very narrow
window at the G1-S transition. It becomes rapidly expressed in late G1 phase and
then degraded very soon after forming a complex with CDK2, by ubiquitin-
mediated proteolysis (Clurman et al. 1996 ; Won and Reed 1996 ). In contrast,
Cyclin A is more stable throughout the cell cycle. It is expressed from early S
phase and its protein levels continue to increase throughout S and G2 phase, during
which the proteins complexes with CDK2 and CDK1, respectively. Cyclin A is
then rapidly degraded during prometaphase (Hunt et al. 1992 ; Pines and Hunter
1990 ). Cyclins have also been reported to contribute to the substrate specificity of
each CDK-cyclin complex (Peeper et al. 1993 ).
Phosphorylation of both CDK and cyclin subunits has been shown to regulate
the level of activity of CDK-cyclin complexes. Phosphorylation of three critical
residues (corresponding to T161, T14 and Y15 in mammalian cells) regulate CDK
activity (Morgan 2007 ) (Fig. 11.2 ). T14 and Y15 phosphorylation by the Wee1
and Myt1 kinases keep the complex in an inactive form (Malumbres and Barbacid
2005 ). The opposing activities of the CDC25 protein phosphatases, which
dephosphorylate CDK on these two residues, activate the complex (Fig. 11.2 ).
Three CDC25 isoforms exist in mammalian cells (CDC25A, B and C), all of which
co-operate to regulate the activities of the various CDK-cyclin complexes
throughout cell division (Boutros et al. 2006 , 2007 ), and all of which are found at
the centrosome (Schmitt et al. 2006 ; Bonnet et al. 2008 ; Shreeram et al. 2008 ).
Phosphorylation of T161 on CDK by CDK-activating kinase (CAK) is required for
full activation of the kinase (Kaldis 1999 ) (Fig. 11.2 ).
CDK activities are also regulated by CDK inhibitors. These bind to and inac-
tivate CDKs, either prior to the requirement of their activity or in response to
cellular stress signals, such as DNA damage. Mammalian cells have a number of
CDK inhibitors, including p21, p27 and p57, which inhibit CDK2 and p15, p16,
p18 and p19 which inhibit CDK4 and CDK6 (Morgan 2007 ).
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