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Toggle switches, pulses and oscillations are intrinsic properties of the Src activation/deactivation cycle.

ABSTRACT: Src-family kinases (SFKs) play a pivotal role in growth factor signaling, mitosis, cell motility and invasiveness. In their basal state, SFKs maintain a closed autoinhibited conformation, where the Src homology 2 domain interacts with an inhibitory phosphotyrosine in the C-terminus. Activation involves dephosphorylation of this inhibitory phosphotyrosine, followed by intermolecular autophosphorylation of a specific tyrosine residue in the activation loop. The spatiotemporal dynamics of SFK activation controls cell behavior, yet these dynamics remain largely uninvestigated. In the present study, we show that the basic properties of the Src activation/deactivation cycle can bring about complex signaling dynamics, including oscillations, toggle switches and excitable behavior. These intricate dynamics do not require imposed external feedback loops and occur at constant activities of Src inhibitors and activators, such as C-terminal Src kinase and receptor-type protein tyrosine phosphatases. We demonstrate that C-terminal Src kinase and receptor-type protein tyrosine phosphatase underexpression or their simultaneous overexpression can transform Src response patterns into oscillatory or bistable responses, respectively. Similarly, Src overexpression leads to dysregulation of Src activity, promoting sustained self-perpetuating oscillations. Distinct types of responses can allow SFKs to trigger different cell-fate decisions, where cellular outcomes are determined by the stimulation threshold and history. Our mathematical model helps to understand the puzzling experimental observations and suggests conditions where these different kinetic behaviors of SFKs can be tested experimentally.

SUBMITTER: Kaimachnikov NP

PROVIDER: S-EPMC2924194 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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Toggle switches, pulses and oscillations are intrinsic properties of the Src activation/deactivation cycle.

Kaimachnikov Nikolai P NP Kholodenko Boris N BN

The FEBS journal 20090801 15

Src-family kinases (SFKs) play a pivotal role in growth factor signaling, mitosis, cell motility and invasiveness. In their basal state, SFKs maintain a closed autoinhibited conformation, where the Src homology 2 domain interacts with an inhibitory phosphotyrosine in the C-terminus. Activation involves dephosphorylation of this inhibitory phosphotyrosine, followed by intermolecular autophosphorylation of a specific tyrosine residue in the activation loop. The spatiotemporal dynamics of SFK activ ...[more]

PMID: 19627364

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Project description:Synthetic constructs in biotechnology, biocomputing, and modern gene therapy interventions are often based on plasmids or transfected circuits which implement some form of "on-off" switch. For example, the expression of a protein used for therapeutic purposes might be triggered by the recognition of a specific combination of inducers (e.g., antigens), and memory of this event should be maintained across a cell population until a specific stimulus commands a coordinated shut-off. The robustness of such a design is hampered by molecular ("intrinsic") or environmental ("extrinsic") noise, which may lead to spontaneous changes of state in a subset of the population and is reflected in the bimodality of protein expression, as measured for example using flow cytometry. In this context, a "majority-vote" correction circuit, which brings deviant cells back into the required state, is highly desirable, and quorum-sensing has been suggested as a way for cells to broadcast their states to the population as a whole so as to facilitate consensus. In this paper, we propose what we believe is the first such a design that has mathematically guaranteed properties of stability and auto-correction under certain conditions. Our approach is guided by concepts and theory from the field of "monotone" dynamical systems developed by M. Hirsch, H. Smith, and others. We benchmark our design by comparing it to an existing design which has been the subject of experimental and theoretical studies, illustrating its superiority in stability and self-correction of synchronization errors. Our stability analysis, based on dynamical systems theory, guarantees global convergence to steady states, ruling out unpredictable ("chaotic") behaviors and even sustained oscillations in the limit of convergence. These results are valid no matter what are the values of parameters, and are based only on the wiring diagram. The theory is complemented by extensive computational bifurcation analysis, performed for a biochemically-detailed and biologically-relevant model that we developed. Another novel feature of our approach is that our theorems on exponential stability of steady states for homogeneous or mixed populations are valid independently of the number N of cells in the population, which is usually very large (N ≫ 1) and unknown. We prove that the exponential stability depends on relative proportions of each type of state only. While monotone systems theory has been used previously for systems biology analysis, the current work illustrates its power for synthetic biology design, and thus has wider significance well beyond the application to the important problem of coordination of toggle switches.

Project description:The circadian clock controls many physiological processes in higher plants and causes a large fraction of the genome to be expressed with a 24h rhythm. The transcripts encoding the RNA-binding proteins AtGRP7 (Arabidopsis thaliana Glycine Rich Protein 7) and AtGRP8 oscillate with evening peaks. The circadian clock components CCA1 and LHY negatively affect AtGRP7 expression at the level of transcription. AtGRP7 and AtGRP8, in turn, negatively auto-regulate and reciprocally cross-regulate post-transcriptionally: high protein levels promote the generation of an alternative splice form that is rapidly degraded. This clock-regulated feedback loop has been proposed to act as a molecular slave oscillator in clock output. While mathematical models describing the circadian core oscillator in Arabidopsis thaliana were introduced recently, we propose here the first model of a circadian slave oscillator. We define the slave oscillator in terms of ordinary differential equations and identify the model's parameters by an optimization procedure based on experimental results. The model successfully reproduces the pertinent experimental findings such as waveforms, phases, and half-lives of the time-dependent concentrations. Furthermore, we obtain insights into possible mechanisms underlying the observed experimental dynamics: the negative auto-regulation and reciprocal cross-regulation via alternative splicing could be responsible for the sharply peaking waveforms of the AtGRP7 and AtGRP8 mRNA. Moreover, our results suggest that the AtGRP8 transcript oscillations are subordinated to those of AtGRP7 due to a higher impact of AtGRP7 protein on alternative splicing of its own and of the AtGRP8 pre-mRNA compared to the impact of AtGRP8 protein. Importantly, a bifurcation analysis provides theoretical evidence that the slave oscillator could be a toggle switch, arising from the reciprocal cross-regulation at the post-transcriptional level. In view of this, transcriptional repression of AtGRP7 and AtGRP8 by LHY and CCA1 induces oscillations of the toggle switch, leading to the observed high-amplitude oscillations of AtGRP7 mRNA.

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Toggle switches, pulses and oscillations are intrinsic properties of the Src activation/deactivation cycle.

Publications

Toggle switches, pulses and oscillations are intrinsic properties of the Src activation/deactivation cycle.

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