Putting One Step Before the Other: Distinct Activation Pathways for Cdk1 and Cdk2 Bring Order to the Mammalian Cell Cycle

Cell Cycle. 2010 Feb 15;9(4):706-14. doi: 10.4161/cc.9.4.10732. Epub 2010 Feb 23.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • CDC2 Protein Kinase / metabolism*
  • Cyclin A / metabolism
  • Cyclin B / metabolism
  • Cyclin-Dependent Kinase 2 / metabolism*
  • DNA Replication
  • Models, Theoretical
  • Phosphorylation
  • Protein Interaction Domains and Motifs
  • S Phase

Substances

  • Cyclin A
  • Cyclin B
  • CDC2 Protein Kinase
  • Cyclin-Dependent Kinase 2