Receptor-based mechanism of relative sensing and cell memory in mammalian signaling networks

  1. Eugenia Lyashenko
  2. Mario Niepel
  3. Purushottam D Dixit
  4. Sang Kyun Lim
  5. Peter K Sorger
  6. Dennis Vitkup  Is a corresponding author
  1. Columbia University, United States
  2. Harvard Medical School, United States

Abstract

Detecting relative rather than absolute changes in extracellular signals enables cells to make decisions in fluctuating environments. However, how mammalian signaling networks store the memories of past stimuli and subsequently use them to compute relative signals, i.e. perform fold change detection, is not well understood. Using the growth factor-activated PI3K-Akt signaling pathway, we develop computational and analytical models, and experimentally validate a novel mechanism of relative sensing in mammalian cells. This mechanism relies on a new form of cellular memory, where cells effectively encode past stimulation levels in the abundance of cognate receptors on the cell surface. We show the robustness and specificity of the relative sensing for two physiologically important ligands, epidermal growth factor (EGF) and hepatocyte growth factor (HGF), and across wide ranges of background stimuli. Our results suggest that similar mechanisms of memory and fold change detection are likely to be important across diverse signaling cascades and biological contexts.

Data availability

All data used in this study and the code used for simulations is available at https://github.com/dixitpd/FoldChange

Article and author information

Author details

  1. Eugenia Lyashenko

    Department of Systems Biology, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Mario Niepel

    HMS LINCS Center, Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1415-6295
  3. Purushottam D Dixit

    Department of Systems Biology, Columbia University, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Sang Kyun Lim

    HMS LINCS Center, Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Peter K Sorger

    HMS LINCS Center, Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3364-1838
  6. Dennis Vitkup

    Department of Systems Biology, Columbia University, New York, United States
    For correspondence
    dv2121@cumc.columbia.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4259-8162

Funding

National Institutes of Health (R01CA201276)

  • Eugenia Lyashenko
  • Purushottam D Dixit
  • Dennis Vitkup

National Institutes of Health (U54CA209997)

  • Eugenia Lyashenko
  • Purushottam D Dixit
  • Dennis Vitkup

National Institutes of Health (U54HL127365)

  • Mario Niepel
  • Sang Kyun Lim
  • Peter K Sorger

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Uri Alon, Weizmann Institute of Science, Israel

Publication history

  1. Received: July 19, 2019
  2. Accepted: December 18, 2019
  3. Accepted Manuscript published: January 21, 2020 (version 1)
  4. Version of Record published: February 27, 2020 (version 2)

Copyright

© 2020, Lyashenko et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Eugenia Lyashenko
  2. Mario Niepel
  3. Purushottam D Dixit
  4. Sang Kyun Lim
  5. Peter K Sorger
  6. Dennis Vitkup
(2020)
Receptor-based mechanism of relative sensing and cell memory in mammalian signaling networks
eLife 9:e50342.
https://doi.org/10.7554/eLife.50342

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