A unified approach to dissecting biphasic responses in cell signalling

  1. Vaidhiswaran Ramesh
  2. J Krishnan  Is a corresponding author
  1. Imperial College London, United Kingdom

Abstract

Biphasic responses are encountered at all levels in biological systems. At the cellular level, biphasic dose-responses are widely encountered in cell signalling and post-translational modification systems and represent safeguards against over-activation or overexpression of species. In this paper we provide a unified theoretical synthesis of biphasic responses in cell signalling systems, by assessing signalling systems ranging from basic biochemical building blocks to canonical network structures to well-characterized exemplars on one hand, and examining different types of doses on the other. By using analytical and computational approaches applied to a range of systems across levels (described by broadly employed models) we reveal (i) design principles enabling the presence of biphasic responses, including in almost all instances, an explicit characterization of the parameter space (ii) structural factors which preclude the possibility of biphasic responses (iii) different combinations of the presence or absence of enzyme-biphasic and substrate-biphasic responses, representing safeguards against overactivation and overexpression respectively (iv) the possibility of broadly robust biphasic responses (v) the complete alteration of signalling behaviour in a network due to biphasic interactions between species (biphasic regulation) (vi) the propensity of different co-existing biphasic responses in the Erk signalling network. These results both individually and in totality have a number of important consequences for systems and synthetic biology.

Data availability

The current manuscript contains results which are computational and analytical (mathematical). These are all presented and discussed in the main text. Maple code was used for establishing the analytical results and this is uploaded as Source Code (Maple) and in pdf format as supplementary files (supplementary file 1 and supplementary file 2). The code for generating the computational results has been deposited at https://github.com/VaidhiswaranR/Work-in-progress--Biphasic2022

Article and author information

Author details

  1. Vaidhiswaran Ramesh

    Department of Chemical Engineerng, Imperial College London, London, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  2. J Krishnan

    Department of Chemical Engineerng, Imperial College London, London, United Kingdom
    For correspondence
    j.krishnan@imperial.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6196-2033

Funding

No external funding was received for this work

Reviewing Editor

  1. Ahmad S Khalil, Boston University, United States

Version history

  1. Received: January 30, 2023
  2. Preprint posted: February 14, 2023 (view preprint)
  3. Accepted: December 5, 2023
  4. Accepted Manuscript published: December 6, 2023 (version 1)
  5. Version of Record published: March 8, 2024 (version 2)

Copyright

© 2023, Ramesh & Krishnan

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.

Metrics

  • 407
    views
  • 99
    downloads
  • 0
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Vaidhiswaran Ramesh
  2. J Krishnan
(2023)
A unified approach to dissecting biphasic responses in cell signalling
eLife 12:e86520.
https://doi.org/10.7554/eLife.86520

Share this article

https://doi.org/10.7554/eLife.86520

Further reading

    1. Developmental Biology
    2. Physics of Living Systems
    Raphaël Clément
    Insight

    Geometric criteria can be used to assess whether cell intercalation is active or passive during the convergent extension of tissue.

    1. Computational and Systems Biology
    2. Physics of Living Systems
    Taegon Chung, Iksoo Chang, Sangyeol Kim
    Research Article

    Locomotion is a fundamental behavior of Caenorhabditis elegans (C. elegans). Previous works on kinetic simulations of animals helped researchers understand the physical mechanisms of locomotion and the muscle-controlling principles of neuronal circuits as an actuator part. It has yet to be understood how C. elegans utilizes the frictional forces caused by the tension of its muscles to perform sequenced locomotive behaviors. Here, we present a two-dimensional rigid body chain model for the locomotion of C. elegans by developing Newtonian equations of motion for each body segment of C. elegans. Having accounted for friction-coefficients of the surrounding environment, elastic constants of C. elegans, and its kymogram from experiments, our kinetic model (ElegansBot) reproduced various locomotion of C. elegans such as, but not limited to, forward-backward-(omega turn)-forward locomotion constituting escaping behavior and delta-turn navigation. Additionally, ElegansBot precisely quantified the forces acting on each body segment of C. elegans to allow investigation of the force distribution. This model will facilitate our understanding of the detailed mechanism of various locomotive behaviors at any given friction-coefficients of the surrounding environment. Furthermore, as the model ensures the performance of realistic behavior, it can be used to research actuator-controller interaction between muscles and neuronal circuits.