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Common effector processing mediates cell-specific responses to stimuli


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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  1. Gerhart, J. 1998 Warkany lecture: signaling pathways in development. Teratology 60, 226–239 (1999)

    Article  CAS  Google Scholar 

  2. Jordan, J. D., Landau, E. M. & Iyengar, R. Signaling networks: the origins of cellular multitasking. Cell 103, 193–200 (2000)

    Article  CAS  Google Scholar 

  3. Downward, J. The ins and outs of signalling. Nature 411, 759–762 (2001)

    Article  ADS  CAS  Google Scholar 

  4. Irish, J. M. et al. Single cell profiling of potentiated phospho-protein networks in cancer cells. Cell 118, 217–228 (2004)

    Article  CAS  Google Scholar 

  5. Wajant, H., Pfizenmaier, K. & Scheurich, P. Tumor necrosis factor signaling. Cell Death Differ. 10, 45–65 (2003)

    Article  CAS  Google Scholar 

  6. Kenakin, T. Predicting therapeutic value in the lead optimization phase of drug discovery. Nature Rev. Drug Discov. 2, 429–438 (2003)

    Article  CAS  Google Scholar 

  7. McCormick, F. Cancer gene therapy: fringe or cutting edge? Nature Rev. Cancer 1, 130–141 (2001)

    Article  CAS  Google Scholar 

  8. Janes, K. A. et al. A systems model of signaling identifies a molecular basis set for cytokine-induced apoptosis. Science 310, 1646–1653 (2005)

    Article  ADS  CAS  Google Scholar 

  9. Schmitz, E. K., Kraus, D. M. & Bulla, G. A. Tissue-specificity of apoptosis in hepatoma-derived cell lines. Apoptosis 9, 369–375 (2004)

    Article  CAS  Google Scholar 

  10. Ohmori, Y. & Hamilton, T. A. Cell type and stimulus specific regulation of chemokine gene expression. Biochem. Biophys. Res. Commun. 198, 590–596 (1994)

    Article  CAS  Google Scholar 

  11. Miller-Jensen, K., Janes, K. A., Wong, Y. L., Griffith, L. G. & Lauffenburger, D. A. Adenoviral vector saturates Akt pro-survival signaling and blocks insulin-mediated rescue of tumor necrosis-factor-induced apoptosis. J. Cell Sci. 119, 3788–3798 (2006)

    Article  CAS  Google Scholar 

  12. Pawson, T. Specificity in signal transduction: from phosphotyrosine-sh2 domain interactions to complex cellular systems. Cell 116, 191–203 (2004)

    Article  CAS  Google Scholar 

  13. Bouwmeester, T. et al. A physical and functional map of the human TNF-α/NF-κB signal transduction pathway. Nature Cell Biol. 6, 97–105 (2004)

    Article  CAS  Google Scholar 

  14. Cho, K. H., Shin, S. Y., Lee, H. W. & Wolkenhauer, O. Investigations into the analysis and modeling of the TNFα-mediated NF-κB-signaling pathway. Genome Res. 13, 2413–2422 (2003)

    Article  CAS  Google Scholar 

  15. Janes, K. A. & Lauffenburger, D. A. A biological approach to computational models of proteomic networks. Curr. Opin. Chem. Biol. 10, 73–80 (2006)

    Article  CAS  Google Scholar 

  16. Philpott, N. J., Nociari, M., Elkon, K. B. & Falck-Pedersen, E. Adenovirus-induced maturation of dendritic cells through a PI3 kinase-mediated TNF-alpha induction pathway. Proc. Natl Acad. Sci. USA 101, 6200–6205 (2004)

    Article  ADS  CAS  Google Scholar 

  17. Liu, T. C. et al. Functional interactions of antiapoptotic proteins and tumor necrosis factor in the context of a replication-competent adenovirus. Gene Ther. 12, 1333–1346 (2005)

    Article  CAS  Google Scholar 

  18. Janes, K. A. et al. The response of human epithelial cells to TNF involves an inducible autocrine cascade. Cell 124, 1225–1239 (2006)

    Article  CAS  Google Scholar 

  19. Gaudet, S. et al. A compendium of signals and responses triggered by prodeath and prosurvival cytokines. Mol. Cell. Proteomics 4, 1569–1590 (2005)

    Article  CAS  Google Scholar 

  20. Janes, K. A. & Yaffe, M. B. Data-driven modelling of signal-transduction networks. Nature Rev. Mol. Cell Biol. 7, 820–828 (2006)

    Article  CAS  Google Scholar 

  21. Nelson, P. J., Kim, H., Manning, W., Goralski, T. & Krensky, A. Genomic organization and transcriptional regulation of the RANTES chemokine gene. J. Immunol. 151, 2601–2612 (1993)

    CAS  PubMed  Google Scholar 

  22. Bowen, G. P. et al. Adenovirus vector-induced inflammation: capsid-dependent induction of the C–C chemokine RANTES requires NF-κB. Hum. Gene Ther. 13, 367–379 (2002)

    Article  CAS  Google Scholar 

  23. Samuel, C. E. Antiviral actions of interferons. Clin. Microbiol. Rev. 14, 778–809 (2001)

    Article  CAS  Google Scholar 

  24. Dancey, J. & Sausville, E. A. Issues and progress with protein kinase inhibitors for cancer treatment. Nature Rev. Drug Discov. 2, 296–313 (2003)

    Article  CAS  Google Scholar 

  25. Luo, J., Manning, B. D. & Cantley, L. C. Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell 4, 257–262 (2003)

    Article  CAS  Google Scholar 

  26. Janes, K. A. et al. A high-throughput quantitative multiplex kinase assay for monitoring information flow in signaling networks: application to sepsis-apoptosis. Mol. Cell. Proteomics 2, 463–473 (2003)

    Article  CAS  Google Scholar 

  27. Karin, M. & Greten, F. R. NF-κB: linking inflammation and immunity to cancer development and progression. Nature Rev. Immunol. 5, 749–759 (2005)

    Article  CAS  Google Scholar 

  28. Csete, M. & Doyle, J. Bow ties, metabolism and disease. Trends Biotechnol. 22, 446–450 (2004)

    Article  CAS  Google Scholar 

  29. Debnath, J., Muthuswamy, S. K. & Brugge, J. S. Morphogenesis and oncogenesis of MCF-10A mammary epithelial acini grown in three-dimensional basement membrane cultures. Methods 30, 256–268 (2003)

    Article  CAS  Google Scholar 

  30. Janes, K. A. et al. Cue-signal-response analysis of TNF-induced apoptosis by partial least squares regression of dynamic multivariate data. J. Comput. Biol. 11, 544–561 (2004)

    Article  CAS  Google Scholar 

  31. Jordan, N. J. et al. Expression of functional CXCR4 chemokine receptors on human colonic epithelial cells. J. Clin. Invest. 104, 1061–1069 (1999)

    Article  CAS  Google Scholar 

  32. Choe, H. et al. The beta-chemokine receptors CCR3 and CCR5 facilitate infection by primary HIV-1 isolates. Cell 85, 1135–1148 (1996)

    Article  CAS  Google Scholar 

  33. Vandesompele, J. et al. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 3, research0034.1–0034.11 (2002)

    Article  Google Scholar 

  34. Lakowicz, J. R. Principles of Fluorescence Spectroscopy 2nd edn 118–124 (Kluwer Academic/Plenum, New York, 1999)

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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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Correspondence to Douglas A. Lauffenburger.

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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).

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