Theoretical analysis reveals a role for RAF conformational autoinhibition in paradoxical activation

  1. Gaurav Mendiratta
  2. Edward Stites  Is a corresponding author
  1. Salk Institute for Biological Studies, United States
  2. Yale University, United States

Abstract

RAF kinase inhibitors can, under certain conditions, increase RAF kinase signaling. This process, which is commonly referred to as 'paradoxical activation' (PA), is incompletely understood. We use mathematical and computational modeling to investigate PA, and we derive rigorous analytical expressions that illuminate the underlying mechanism of this complex phenomenon. We find that conformational autoinhibition modulation by a RAF inhibitor could be sufficient to create PA. We find that experimental RAF-inhibitor drug dose response data that characterize PA across different types of RAF inhibitors are best explained by a model that includes RAF-inhibitor modulation of three properties: conformational autoinhibition, dimer affinity, and drug binding within the dimer (i.e., negative cooperativity). Overall, this work establishes conformational autoinhibition as a robust mechanism for RAF-inhibitor driven PA based solely on equilibrium dynamics of canonical interactions that comprise RAF signaling and inhibition.

Data availability

All data needed to evaluate the conclusions in the paper are present in the paper or the Supplementary Materials. All materials are available upon request from the corresponding author.

Article and author information

Author details

  1. Gaurav Mendiratta

    Integrative Biology Laboratory, Salk Institute for Biological Studies, La Jolla, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5091-348X
  2. Edward Stites

    Department of Laboratory Medicine, Yale University, New Haven, United States
    For correspondence
    edward.stites@yale.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3783-7336

Funding

National Institutes of Health (K22CA216318)

  • Edward Stites

National Institutes of Health (DP2AT011327)

  • Edward Stites

Melanoma Research Alliance (Young Investigator Award)

  • Edward Stites

Joe W. and Dorothy Dorsett Brown Foundation (N/A)

  • Edward Stites

Salk Institute for Biological Studies

  • Gaurav Mendiratta

Conrad Prebys Foundation (N/A)

  • Edward Stites

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

Reviewing Editor

  1. Natalia Jura, University of California, San Francisco, United States

Version history

  1. Preprint posted: November 20, 2019 (view preprint)
  2. Received: August 16, 2022
  3. Accepted: October 10, 2023
  4. Accepted Manuscript published: October 12, 2023 (version 1)
  5. Version of Record published: November 6, 2023 (version 2)

Copyright

© 2023, Mendiratta & Stites

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. Gaurav Mendiratta
  2. Edward Stites
(2023)
Theoretical analysis reveals a role for RAF conformational autoinhibition in paradoxical activation
eLife 12:e82739.
https://doi.org/10.7554/eLife.82739

Share this article

https://doi.org/10.7554/eLife.82739

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