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

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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.

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Benjamin Groves

Department of Electrical Engineering, University of Washington, Seattle, United States

Competing interests
The authors declare that no competing interests exist.
Arjun Khakhar

Department of Bioengineering, University of Washington, Seattle, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-4676-6533
Cory Nadel

Department of Pharmacology, University of Washington, Seattle, United States

Competing interests
The authors declare that no competing interests exist.
Richard Gardner

Department of Pharmacology, University of Washington, Seattle, United States

Competing interests
The authors declare that no competing interests exist.
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.

"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.

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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.