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Sci. Signal., 11 October 2011
Vol. 4, Issue 194, p. ra67
[DOI: 10.1126/scisignal.2002152]


Load-Induced Modulation of Signal Transduction Networks

Peng Jiang1, Alejandra C. Ventura2, Eduardo D. Sontag3, Sofia D. Merajver4, Alexander J. Ninfa1*, and Domitilla Del Vecchio5*

1 Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI 48109–0606, USA.
2 Institute for Physiology, Molecular Biology, and Neuroscience, Department of Biology, and Laboratorio de Fisiología y Biología Molecular, Departamento de Fisiología, Biología Molecular y Celular, IFIBYNE-CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Ciudad Universitaria, Pabellón 2, Buenos Aires C1428EHA, Argentina.
3 Department of Mathematics, Rutgers University, New Brunswick, NJ 08854–8019, USA.
4 Department of Internal Medicine, Comprehensive Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.
5 Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.

Abstract: Biological signal transduction networks are commonly viewed as circuits that pass along information—in the process amplifying signals, enhancing sensitivity, or performing other signal-processing tasks—to transcriptional and other components. Here, we report on a "reverse-causality" phenomenon, which we call load-induced modulation. Through a combination of analytical and experimental tools, we discovered that signaling was modulated, in a surprising way, by downstream targets that receive the signal and, in doing so, apply what in physics is called a load. Specifically, we found that non-intuitive changes in response dynamics occurred for a covalent modification cycle when load was present. Loading altered the response time of a system, depending on whether the activity of one of the enzymes was maximal and the other was operating at its minimal rate or whether both enzymes were operating at submaximal rates. These two conditions, which we call "limit regime" and "intermediate regime," were associated with increased or decreased response times, respectively. The bandwidth, the range of frequency in which the system can process information, decreased in the presence of load, suggesting that downstream targets participate in establishing a balance between noise-filtering capabilities and a circuit’s ability to process high-frequency stimulation. Nodes in a signaling network are not independent relay devices, but rather are modulated by their downstream targets.

* To whom correspondence should be addressed. E-mail: aninfa{at} (A.J.N.); ddv{at} (D.D.V.)

Citation: P. Jiang, A. C. Ventura, E. D. Sontag, S. D. Merajver, A. J. Ninfa, D. Del Vecchio, Load-Induced Modulation of Signal Transduction Networks. Sci. Signal. 4, ra67 (2011).

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Comment on "Load-Induced Modulation of Signal Transduction Networks": Reconciling Ultrasensitivity with Bifunctionality?.
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Science Signaling 5, lc1
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Response to Comment on "'Load-Induced Modulation of Signal Transduction Networks': Reconciling Ultrasensitivity with Bifunctionality?".
P. Jiang, A. C. Ventura, E. D. Sontag, S. D. Merajver, A. J. Ninfa, and D. Del Vecchio (2012)
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