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Biophysical Journal 86:3432-3443 (2004)
© 2004 The Biophysical Society

Multisite Phosphorylation and Network Dynamics of Cyclin-Dependent Kinase Signaling in the Eukaryotic Cell Cycle

Ling Yang * {dagger}, W. Robb MacLellan * {dagger} {ddagger}, Zhangang Han * {dagger}, James N. Weiss * {dagger} {ddagger} and Zhilin Qu * {dagger}

* Cardiovascular Research Laboratory, {dagger} Departments of Medicine (Cardiology) and {ddagger} Physiology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California 90095

Correspondence: Address reprint requests to Zhilin Qu, PhD, Dept. of Medicine (Cardiology), David Geffen School of Medicine at UCLA, 47-123 CHS, 10833 Le Conte Ave., Los Angeles, CA 90095. Tel.: 310-794-7027; Fax: 310-206-9133; E-mail: zqu{at}mednet.ucla.edu.

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.




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