Multisite phosphorylation and network dynamics of cyclin-dependent kinase signaling in the eukaryotic cell cycle.
Multisite phosphorylation of regulatory proteins has been proposed to underlie ultrasensitive responses required to generate nontrivial dynamics in complex biological signaling networks. We used a random search strategy to analyze the role of multisite phosphorylation of key proteins regulating cyclin-dependent kinase (CDK) activity in a model of the eukaryotic cell cycle. We show that multisite phosphorylation of either CDK, CDC25, wee1, or CDK-activating kinase is sufficient to generate dynamical behaviors including bistability and limit cycles. Moreover, combining multiple feedback loops based on multisite phosphorylation do not destabilize the cell cycle network by inducing complex behavior, but rather increase the overall robustness of the network. In this model we find that bistability is the major dynamical behavior of the CDK signaling network, and that negative feedback converts bistability into limit cycle behavior. We also compare the dynamical behavior of several simplified models of CDK regulation to the fully detailed model. In summary, our findings suggest that multisite phosphorylation of proteins is a critical biological mechanism in generating the essential dynamics and ensuring robust behavior of the cell cycle.
Yang
Ling
L
Departments of Medicine (Cardiology) and Physiology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California 90095, USA.
MacLellan
W Robb
WR
Han
Zhangang
Z
Weiss
James N
JN
Qu
Zhilin
Z
D002453:Cell Cycle / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D003198:Computer Simulation; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D016213:Cyclins / Q000378:metabolism*; D006801:Humans; D008962:Models, Theoretical; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
D018797:Cell Cycle Proteins; D016213:Cyclins; D009687:Nuclear Proteins; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; D018844:Cyclin-Dependent Kinases