Rewiring MAP kinases in Saccharomyces cerevisiae to regulate novel targets through ubiquitination

  1. Benjamin Groves
  2. Arjun Khakhar
  3. Cory Nadel
  4. Richard Gardner
  5. Georg Seelig  Is a corresponding author
  1. University of Washington, United States

Abstract

Evolution has often copied and repurposed the mitogen-activated protein kinase (MAPK) signaling module. Understanding how connections form during evolution, in disease and across individuals requires knowledge of the basic tenets that govern kinase-substrate interactions. We identify criteria sufficient for establishing regulatory links between a MAPK and a non-native substrate. The yeast MAPK Fus3 and human MAPK ERK2 can be functionally redirected if only two conditions are met: the kinase and substrate contain matching interaction domains and the substrate includes a phospho-motif that can be phosphorylated by the kinase and recruit a downstream effector. We used a panel of interaction domains and phosphorylation-activated degradation motifs to demonstrate modular and scalable retargeting. We applied our approach to reshape the signaling behavior of an existing kinase pathway. Together, our results demonstrate that a MAPK can be largely defined by its interaction domains and compatible phospho-motifs and provide insight into how MAPK-substrate connections form.

Article and author information

Author details

  1. Benjamin Groves

    Department of Electrical Engineering, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Arjun Khakhar

    Department of Bioengineering, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4676-6533
  3. Cory Nadel

    Department of Pharmacology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Richard Gardner

    Department of Pharmacology, University of Washington, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Georg Seelig

    Department of Computer Science and Engineering, University of Washington, Seattle, United States
    For correspondence
    gseelig@uw.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3163-8782

Funding

National Science Foundation (EFMA-1137266)

  • Georg Seelig

WRF-IPD Innovations Fellows Program

  • Benjamin Groves

National Science Foundation (CCF-1317653)

  • Georg Seelig

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

Reviewing Editor

  1. Ivan Dikic, Goethe University Medical School, Germany

Version history

  1. Received: February 12, 2016
  2. Accepted: August 14, 2016
  3. Accepted Manuscript published: August 15, 2016 (version 1)
  4. Version of Record published: September 12, 2016 (version 2)
  5. Version of Record updated: September 26, 2016 (version 3)

Copyright

© 2016, Groves 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. Benjamin Groves
  2. Arjun Khakhar
  3. Cory Nadel
  4. Richard Gardner
  5. Georg Seelig
(2016)
Rewiring MAP kinases in Saccharomyces cerevisiae to regulate novel targets through ubiquitination
eLife 5:e15200.
https://doi.org/10.7554/eLife.15200

Share this article

https://doi.org/10.7554/eLife.15200

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