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3.2 Cyclin-Dependent Kinases (Cdks)
The common feature of all Cdks is that their kinase activity depends on association
with a regulatory cyclin subunit. Of the roughly one dozen Cdks identified in mam-
malian cells, five — Cdk1, Cdk2, Cdk3, Cdk4 and Cdk6 — are directly involved in
cell cycle regulation (Malumbres and Barbacid 2005 ). Notably, mouse knockout
studies identified Cdk1, also known as cell division cycle protein 2 (Cdc2), as the
only cell cycle Cdk that is essential for cell division, i.e. mice lacking functional
Cdk1 did not develop beyond the two-cell stage, whereas, for example, Cdk2−/− mice
were viable, but sterile (Santamaria et al. 2007 ). Structural studies on human Cdk2
provided the molecular explanation for the requirement of cyclin binding for kinase
activity. Cdk2 shares with other Ser/Thr protein kinases a two-lobed structure where
the catalytic site that binds ATP is sandwiched between a short amino- terminal and a
Interphase M-phase Interphasesubstratesmitotic kinases
substrates
phosphatasesPsubstratesmitotic kinases
substrates
phosphatasesPFig. 3.2 To achieve cell cycle transitions, mitotic kinases and antagonising phosphatases must be
regulated in a manner such that their activities are mutually exclusive
● Nuclear envelope breakdown● DNA replication
● Centrosome duplication
MPFPhosphatasesSubstrates-PInterphase M-phase Interphase● Chromosome condensation● Cell growth ● Golgi breakdown
● Nuclear envelope reformation
● Spindle disassembly● Chromosome decondensation
● Golgi reassembly
● Spindle assemblyFig. 3.1 Cell cycle transitions are mediated by changes in the phosphorylation state of the cell
division machinery. Key cell cycle events such as chromosome condensation and nuclear envelope
breakdown are triggered by the phosphorylation of structural as well as regulatory cell cycle pro-
teins (substrate P). Reversal of these processes depends on the dephosphorylation of mitotic
phosphoproteins
A. Heim et al.