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Common effector processing mediates cell-specific responses to stimuli

Nature volume 448, pages 604–608 (2007)Cite this article

Abstract

The fundamental components of many signalling pathways are common to all cells1,2,3. However, stimulating or perturbing the intracellular network often causes distinct phenotypes that are specific to a given cell type4,5. This ‘cell specificity’ presents a challenge in understanding how intracellular networks regulate cell behaviour and an obstacle to developing drugs that treat signalling dysfunctions6,7. Here we apply a systems-modelling approach8 to investigate how cell-specific signalling events are integrated through effector proteins to cause cell-specific outcomes. We focus on the synergy between tumour necrosis factor and an adenoviral vector as a therapeutically relevant stimulus that induces cell-specific responses9,10,11. By constructing models that estimate how kinase-signalling events are processed into phenotypes through effector substrates, we find that accurate predictions of cell specificity are possible when different cell types share a common ‘effector-processing’ mechanism. Partial-least-squares regression models based on common effector processing accurately predict cell-specific apoptosis, chemokine release, gene induction, and drug sensitivity across divergent epithelial cell lines. We conclude that cell specificity originates from the differential activation of kinases and other upstream transducers, which together enable different cell types to use common effectors to generate diverse outcomes. The common processing of network signals by downstream effectors points towards an important cell biological principle, which can be applied to the understanding of cell-specific responses to targeted drug therapies6.

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Figure 1: Test of a common effector-processing hypothesis in epithelial cells treated with Adv plus TNF.
Figure 2: Principal components of the common-processing model reveal cell-specific IFN responses to treatment with Adv plus TNF.
Figure 3: Common effector processing uniquely predicts resistance of Adv-infected HeLa cells to PI(3)K inhibition.
Figure 4: Deduction of cell-specific sensitivity to early-phase IKK inhibition.

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Acknowledgements

We thank G. Hoffman, K. Haigis and members of the Lauffenburger and Brugge laboratories for comments on the manuscript. This work was supported by grants from the NIGMS Cell Decision Processes Center, the USCB-CalTech-MIT Institute for Collaborative Biotechnologies, and the MIT Biotechnology Process Engineering Center to D.A.L. K.A.J. acknowledges support from the American Cancer Society (New England Division – SpinOdyssey).

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Author notes

  1. Kathryn Miller-Jensen and Kevin A. Janes: These authors contributed equally to this work.

Authors and Affiliations

  1. Center for Cell Decision Processes, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA,

    Kathryn Miller-Jensen, Kevin A. Janes & Douglas A. Lauffenburger

  2. Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA,

    Kathryn Miller-Jensen & Douglas A. Lauffenburger

  3. Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA,

    Kevin A. Janes & Joan S. Brugge

  4. Departments of Biology and Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA,

    Douglas A. Lauffenburger

Authors
  1. Kathryn Miller-Jensen
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Correspondence to Douglas A. Lauffenburger.

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Supplementary Information

This file contains Supplementary Methods, Supplementary Figures S1-S15 with Legends, Supplementary Tables S1-S6, and additional references. (PDF 604 kb)

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Miller-Jensen, K., Janes, K., Brugge, J. et al. Common effector processing mediates cell-specific responses to stimuli. Nature 448, 604–608 (2007). https://doi.org/10.1038/nature06001

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