Incoherent feedforward control governs adaptation of activated ras in a eukaryotic chemotaxis pathway.
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.
Section of Cell and Developmental Biology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
Kosuke
K
Takeda
Danying
D
Shao
Micha
M
Adler
Pascale G
PG
Charest
William F
WF
Loomis
Herbert
H
Levine
Alex
A
Groisman
Wouter-Jan
WJ
Rappel
Richard A
RA
Firtel
D000222:Adaptation, Physiological / Q000502:physiology*; D002630:Chemotactic Factors / Q000378:metabolism; D002633:Chemotaxis / Q000502:physiology*; D000242:Cyclic AMP / Q000378:metabolism; D004023:Dictyostelium / Q000502:physiology*; D025461:Feedback, Physiological / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
D002630:Chemotactic Factors; D043562:Receptors, G-Protein-Coupled; D049452:Green Fluorescent Proteins; D000242:Cyclic AMP; D018631:ras Proteins