title: 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.
authors.affiliation: Department of Electrical Engineering, University of Washington, Seattle, United States.
authors.forename: Benjamin
authors.identifier: 0000-0002-4827-5500
authors.initials: B
authors.lastname: Groves
authors.affiliation: Department of Bioengineering, University of Washington, Seattle, United States.
authors.forename: Arjun
authors.identifier: 0000-0002-4676-6533
authors.initials: A
authors.lastname: Khakhar
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, United States.
authors.forename: Cory M
authors.initials: CM
authors.lastname: Nadel
authors.affiliation: Department of Pharmacology, University of Washington, Seattle, United States.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Gardner
authors.affiliation: Department of Electrical Engineering, University of Washington, Seattle, United States.|Department of Computer Science and Engineering, University of Washington, Seattle, United States.
authors.forename: Georg
authors.identifier: 0000-0002-3163-8782
authors.initials: G
authors.lastname: Seelig
mesh_terms: D005786:Gene Expression Regulation; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics* / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D054875:Ubiquitination
chemical_list: D011994:Recombinant Proteins; D029701:Saccharomyces cerevisiae Proteins; C075580:FUS3 protein, S cerevisiae; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases
keywords: MAP Kinase; S. cerevisiae; cell biology; computational biology; kinase signaling; synthetic biology; systems biology; ubiquitin