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

Benjamin Groves, Arjun Khakhar, Cory M. Nadel, Richard G. Gardner, Georg Seelig

Research output: Contribution to journalArticle

2 Scopus citations

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.

Original languageEnglish (US)
Article numbere15200
JournaleLife
Volume5
Issue numberAUGUST
DOIs
StatePublished - Aug 15 2016

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