Putting one step before the other: distinct activation pathways for Cdk1 and Cdk2 bring order to the mammalian cell cycle.
Eukaryotic cell division is controlled by the activity of cyclin-dependent kinases (CDKs). Cdk1 and Cdk2, which function at different stages of the mammalian cell cycle, both require cyclin-binding and phosphorylation of the activation (T-) loop for full activity, but differ with respect to the order in which the two steps occur in vivo. To form stable complexes with either of its partners-cyclins A and B-Cdk1 must be phosphorylated on its T-loop, but that phosphorylation in turn depends on the presence of cyclin. Cdk2 can follow a kinetically distinct path to activation in which T-loop phosphorylation precedes cyclin-binding, and thereby out-compete the more abundant Cdk1 for limiting amounts of cyclin A. Mathematical modeling suggests this could be a principal basis for the temporal ordering of CDK activation during S phase, which may dictate the sequence in which replication origins fire. Still to be determined are how: (1) the activation machinery discriminates between closely related CDKs, and (2) coordination of the cell cycle is affected when this mechanism of pathway insulation breaks down.
Department of Structural and Chemical Biology, Mount Sinai School of Medicine, New York, NY, USA.
Karl A
KA
Merrick
Robert P
RP
Fisher
D016203:CDC2 Protein Kinase / Q000378:metabolism*; D019925:Cyclin A / Q000378:metabolism; D019926:Cyclin B / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism*; D004261:DNA Replication; D008962:Models, Theoretical; D010766:Phosphorylation; D054730:Protein Interaction Domains and Motifs; D016196:S Phase
D019925:Cyclin A; D019926:Cyclin B; D016203:CDC2 Protein Kinase; D051357:Cyclin-Dependent Kinase 2