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Jensen KJ, Moyer CB, Janes KA. Network Architecture Predisposes an Enzyme to Either Pharmacologic or Genetic Targeting. Cell Syst. 2016;2(2):112-121doi: 10.1016/j.cels.2016.01.012.
Jensen, K. J., Moyer, C. B., & Janes, K. A. (2016). Network Architecture Predisposes an Enzyme to Either Pharmacologic or Genetic Targeting. Cell systems, 2(2), 112-121. https://doi.org/10.1016/j.cels.2016.01.012
Jensen, Karin J, et al. "Network Architecture Predisposes an Enzyme to Either Pharmacologic or Genetic Targeting." Cell systems vol. 2,2 (2016): 112-121. doi: https://doi.org/10.1016/j.cels.2016.01.012
Jensen KJ, Moyer CB, Janes KA. Network Architecture Predisposes an Enzyme to Either Pharmacologic or Genetic Targeting. Cell Syst. 2016 Feb 24;2(2):112-121. doi: 10.1016/j.cels.2016.01.012. PMID: 26942229; PMCID: PMC4770809.
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Cell Syst. 2016 Feb 24;2(2):112-121. doi: 10.1016/j.cels.2016.01.012.

Network Architecture Predisposes an Enzyme to Either Pharmacologic or Genetic Targeting.

Cell systems

Karin J Jensen, Christian B Moyer, Kevin A Janes

Affiliations

  1. Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA; Sanofi Oncology, Cambridge, MA 02139, USA.
  2. Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA; Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
  3. Department of Biomedical Engineering, University of Virginia, Charlottesville, VA 22908, USA.

PMID: 26942229 PMCID: PMC4770809 DOI: 10.1016/j.cels.2016.01.012

Abstract

Chemical inhibition and genetic knockdown of enzymes are not equivalent in cells, but network-level mechanisms that cause discrepancies between knockdown and inhibitor perturbations are not understood. Here we report that enzymes regulated by negative feedback are robust to knockdown but susceptible to inhibition. Using the Raf-MEK-ERK kinase cascade as a model system, we find that ERK activation is resistant to genetic knockdown of MEK but susceptible to a comparable degree of chemical MEK inhibition. We demonstrate that negative feedback from ERK to Raf causes this knockdown-versus-inhibitor discrepancy in vivo. Exhaustive mathematical modeling of three-tiered enzyme cascades suggests that this result is general: negative autoregulation or feedback favors inhibitor potency, whereas positive autoregulation or feedback favors knockdown potency. Our findings provide a rationale for selecting pharmacologic versus genetic perturbations in vivo and point out the dangers of using knockdown approaches in search of drug targets.

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