Control Analysis of Periodic Phenomena in Biological Systems

Kholodenko, Boris N.; Demin, Oleg; Westerhoff, Hans V.

doi:10.1021/jp962336u

Cited by 57 publications

(77 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…An obvious question is why some, but not all, protein kinases are arranged in cascades, with multiple cycles of phosphorylation and dephosphorylation. A number of theoretical studies [19][20][21][22] have addressed the possibility that this arrangement might produce an ultrasensitive response, defined as a response where a change from 10 % to 90 % of the maximal one requires a change in the initial signal of less than 81-fold, as is the case in a hyperbolic system [23]. Chock and Stadtman [19] pointed out that ultrasensitivity is possible when the activating signal acts at more than one step in a cascade (multistep ultrasensitivity).…”

Section: Scheme 1 the Ampk Cascade Is Activated By Amp Via Four Mechamentioning

confidence: 99%

AMP-activated protein kinase: an ultrasensitive system for monitoring cellular energy charge

Hardie

Salt

Hawley

et al. 1999

Biochemical Journal

263

109

View full text Add to dashboard Cite

The AMP-activated protein kinase cascade is activated by elevation of AMP and depression of ATP when cellular energy charge is compromised, leading to inhibition of anabolic pathways and activation of catabolic pathways. Here we show that the system responds in intact cells in an ultrasensitive manner over a critical range of nucleotide concentrations, in that only a 6-fold increase in activating nucleotide is required in order for the maximal activity of the kinase to progress from 10 % to 90 %, equivalent to a co-operative system with a Hill coefficient (h) of

show abstract

Section: Scheme 1 the Ampk Cascade Is Activated By Amp Via Four Mechamentioning

confidence: 99%

AMP-activated protein kinase: an ultrasensitive system for monitoring cellular energy charge

Hardie

Salt

Hawley

et al. 1999

Biochemical Journal

263

109

View full text Add to dashboard Cite

show abstract

“…As an approach to studying cellular networks, we developed a form of ''top-down'' sensitivity analysis to quantify the input-output relations and molecular interactions in regulatory networks (9). The control of the input signal over the output target was quantified as the ratio of the input-to-output changes at steady state (called the response coefficient in the limit of infinitesimal changes).…”

mentioning

confidence: 99%

Untangling the wires: A strategy to trace functional interactions in signaling and gene networks

Kholodenko

Kiyatkin²,

Bruggeman³

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

388

488

View full text Add to dashboard Cite

Emerging technologies have enabled the acquisition of large genomics and proteomics data sets. However, current methodologies for analysis do not permit interpretation of the data in ways that unravel cellular networking. We propose a quantitative method for determining functional interactions in cellular signaling and gene networks. It can be used to explore cell systems at a mechanistic level or applied within a ''modular'' framework, which dramatically decreases the number of variables to be assayed. This method is based on a mathematical derivation that demonstrates how the topology and strength of network connections can be retrieved from experimentally measured network responses to successive perturbations of all modules. Importantly, our analysis can reveal functional interactions even when the components of the system are not all known. Under these circumstances, some connections retrieved by the analysis will not be direct but correspond to the interaction routes through unidentified elements. The method is tested and illustrated by using computer-generated responses of a modeled mitogen-activated protein kinase cascade and gene network.

show abstract

“…An important reason is the lack of a quantitative description of EGFR signaling network, which hampers a careful examination of the influence of multiple factors. Detailed understanding of the dynamics of complex cellular responses requires a combination of experimental and computational approaches (17)(18)(19).…”

mentioning

confidence: 99%

Quantification of Short Term Signaling by the Epidermal Growth Factor Receptor

Kholodenko¹,

Demin²,

Moehren³

et al. 1999

Journal of Biological Chemistry

Self Cite

537

608

View full text Add to dashboard Cite

During the past decade, our knowledge of molecular mechanisms involved in growth factor signaling has proliferated almost explosively. However, the kinetics and control of information transfer through signaling networks remain poorly understood. This paper combines experimental kinetic analysis and computational modeling of the short term pattern of cellular responses to epidermal growth factor (EGF) in isolated hepatocytes. The experimental data show transient tyrosine phosphorylation of the EGF receptor (EGFR) and transient or sustained response patterns in multiple signaling proteins targeted by EGFR. Transient responses exhibit pronounced maxima, reached within 15-30 s of EGF stimulation and followed by a decline to relatively low (quasi-steady-state) levels. In contrast to earlier suggestions, we demonstrate that the experimentally observed transients can be accounted for without requiring receptor-mediated activation of specific tyrosine phosphatases, following EGF stimulation. The kinetic model predicts how the cellular response is controlled by the relative levels and activity states of signaling proteins and under what conditions activation patterns are transient or sustained. EGFR signaling patterns appear to be robust with respect to variations in many elemental rate constants within the range of experimentally measured values. On the other hand, we specify which changes in the kinetic scheme, rate constants, and total amounts of molecular factors involved are incompatible with the experimentally observed kinetics of signal transfer. Quantitation of signaling network responses to growth factors allows us to assess how cells process information controlling their growth and differentiation.

show abstract

Control Analysis of Periodic Phenomena in Biological Systems

Cited by 57 publications

References 47 publications

AMP-activated protein kinase: an ultrasensitive system for monitoring cellular energy charge

AMP-activated protein kinase: an ultrasensitive system for monitoring cellular energy charge

Untangling the wires: A strategy to trace functional interactions in signaling and gene networks

Quantification of Short Term Signaling by the Epidermal Growth Factor Receptor

Contact Info

Product

Resources

About