Rewiring MAP kinases in Saccharomyces cerevisiae to regulate novel targets through ubiquitination
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
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
- Ivan Dikic, Goethe University Medical School, Germany
Publication history
- Received: February 12, 2016
- Accepted: August 14, 2016
- Accepted Manuscript published: August 15, 2016 (version 1)
- Version of Record published: September 12, 2016 (version 2)
- 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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