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Sci. Signal., 3 January 2012
Vol. 5, Issue 205, p. ra2
[DOI: 10.1126/scisignal.2002413]

RESEARCH ARTICLES

Incoherent Feedforward Control Governs Adaptation of Activated Ras in a Eukaryotic Chemotaxis Pathway

Kosuke Takeda1, Danying Shao2, Micha Adler3, Pascale G. Charest1, William F. Loomis1, Herbert Levine2, Alex Groisman3, Wouter-Jan Rappel2*, and Richard A. Firtel1*

1 Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
2 Department of Physics, University of California, San Diego, La Jolla, CA 92093, USA.
3 Center for Theoretical Biological Physics, University of California, San Diego, La Jolla, CA 92093, USA.

Abstract: Adaptation in signaling systems, during which the output returns to a fixed baseline after a change in the input, often involves negative feedback loops and plays a crucial role in eukaryotic chemotaxis. We determined the dynamical response to a uniform change in chemoattractant concentration of a eukaryotic chemotaxis pathway immediately downstream from G protein–coupled receptors. The response of an activated Ras showed near-perfect adaptation, leading us to attempt to fit the results using mathematical models for the two possible simple network topologies that can provide perfect adaptation. Only the incoherent feedforward network accurately described the experimental results. This analysis revealed that adaptation in this Ras pathway is achieved through the proportional activation of upstream components and not through negative feedback loops. Furthermore, these results are consistent with a local excitation, global inhibition mechanism for gradient sensing, possibly with a Ras guanosine triphosphatase–activating protein acting as a global inhibitor.

* To whom correspondence should be addressed. E-mail: rappel{at}physics.ucsd.edu (W.-J.R.); rafirtel{at}ucsd.edu (R.A.F.)

Citation: K. Takeda, D. Shao, M. Adler, P. G. Charest, W. F. Loomis, H. Levine, A. Groisman, W.-J. Rappel, R. A. Firtel, Incoherent Feedforward Control Governs Adaptation of Activated Ras in a Eukaryotic Chemotaxis Pathway. Sci. Signal. 5, ra2 (2012).

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