Modularity of MAP kinases allows deformation of their signalling pathways

Abstract

Eukaryotic protein kinase pathways have both grown in number and changed their network architecture during evolution. We wondered if there are pivotal proteins in these pathways that have been repeatedly responsible for forming new connections through evolution, thus changing the topology of the network; and if so, whether the underlying properties of these proteins could be exploited to re-engineer and rewire these pathways. We addressed these questions in the context of the mitogen-activated protein kinase (MAPK) pathways. MAPK proteins were found to have repeatedly acquired new specificities and interaction partners during evolution, suggesting that these proteins are pivotal in the kinase network. Using the MAPKs Fus3 and Hog1 of the Saccharomyces cerevisiae mating and hyper-osmolar pathways, respectively, we show that these pivotal proteins can be re-designed to achieve a wide variety of changes in the input-output properties of the MAPK network. Through an analysis of our experimental results and of the sequence and structure of these proteins, we show that rewiring of the network is possible due to the underlying modular design of the MAPKs. We discuss the implications of our findings on the radiation of MAPKs through evolution and on how these proteins achieve their specificity.

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Figure 1: Conservation of downstream components in the pheromone and hyper-osmolar glycerol pathways in S. cerevisiae.
Figure 2: Evolutionary history of MAPKs and their interacting partners.
Figure 3: Sequence analysis of MAPKs Fus3 and Hog1.
Figure 4: Several hybrid MAPKs function in vivo to faithfully transduce and cross-wire the pheromone and hyper-osmolar signals.
Figure 5: Modular design allows some hybrid MAPKs to be activated by either input and others capable of activating either output.

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Acknowledgements

We thank B. Stern for critical readings and suggestions, H. Dohlman, A. Drummond, M. DePristo, A. Murray, D. Huse, D. Fisher, M. McClean, M. Thomson and I. Nachman for discussions and comments, and R.e Hellmiss for help with figures. Work was supported by an NIH grant (2P50GM068763).

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A. M. and S. R. conceived and planned the project and wrote the manuscript. A.M. designed and implemented the computational aspects of the project, performed the microscopy and analysed the data. J.W. and A.M. performed the strain and plasmid construction.

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Correspondence to Sharad Ramanathan.

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The authors declare no competing financial interests.

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Mody, A., Weiner, J. & Ramanathan, S. Modularity of MAP kinases allows deformation of their signalling pathways. Nat Cell Biol 11, 484–491 (2009). https://doi.org/10.1038/ncb1856

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