Light-based feedback for controlling intracellular signaling dynamics


The ability to apply precise inputs to signaling species in live cells would be transformative for interrogating and understanding complex cell-signaling systems. Here we report an 'optogenetic' method for applying custom signaling inputs using feedback control of a light-gated protein-protein interaction. We applied this strategy to perturb protein localization and phosphoinositide 3-kinase activity, generating time-varying signals and clamping signals to buffer against cell-to-cell variability or changes in pathway activity.

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Figure 1: Feedback control to modulate plasma-membrane recruitment of PIF-tagged inputs.
Figure 2: Feedback control can decrease cell-to-cell variability in the optogenetic response.
Figure 3: Feedback control can clamp PIP3 levels against cellular perturbations.


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We thank all members of the Weiner and Lim laboratories, A. Levskaya, A. Edelstein and N. Stuurman for helpful comments and discussions, and A. Loewer and H. El-Samad for critically reading this manuscript. TagBFP construct was a gift from members of the Vale lab (University of California San Francisco), pHR lentiviral vectors were provided by J.R. James (University of California San Francisco), and the iSH construct was a gift from members of the Meyer lab (Stanford University). This work was supported by a Cancer Research Institute Postdoctoral Fellowship to J.E.T., an American Cancer Society postdoctoral fellowship to D.G., the Howard Hughes Medical Institute and US National Institutes of Health grants GM55040, GM62583, EY016546 and P50GM081879 to W.A.L., and a National Institutes of Health grant GM084040 and a Searle Scholars Fellowship to O.D.W.

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J.E.T. conceived and implemented the feedback controller. O.D.W. and W.A.L. supervised the project. All authors designed experiments, which J.E.T. and D.G. performed. J.E.T. analyzed data. J.E.T., W.A.L. and O.D.W. wrote the paper, which all authors edited.

Corresponding authors

Correspondence to Wendell A Lim or Orion D Weiner.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–9, Supplementary Note 1 (PDF 1401 kb)

Supplementary Software 1

Matlab toolbox for microscope control (via Micro-Manager) and the feedback controller. (ZIP 28 kb)

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Toettcher, J., Gong, D., Lim, W. et al. Light-based feedback for controlling intracellular signaling dynamics. Nat Methods 8, 837–839 (2011).

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