Abstract
Mitogen-activated protein kinases (MAPK) are ancestral kinases that form essential signalling cascades. However, scaffolds that recruit kinases to subcellular locations and promote signal transduction have only been described in a few species. Notably, no scaffold was thought necessary for the MAPK cascade promoting sexual differentiation in fission yeast. Here, we identify the hemi-arrestin protein Sms1 as a novel scaffold of this MAPK cascade. Interactions with PIP2 and the pheromone receptor–coupled Gα subunit target Sms1 to plasma membrane patches, where it assembles the active cascade by binding each MAP kinase. These interactions are essential for signal transduction and local signal interpretation for polarised growth. Phosphorylation, including by the MAPK itself, antagonises Sms1 membrane translocation, establishing a negative feedback that underlies polarity patch turnover and prevents untimely mating attempts. Thus, Sms1 is a MAPK scaffold with canonical functions despite its distinct structural fold, highlighting convergent evolution of MAPK scaffolds across eukaryotes.
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Data availability
Source data for all western blots and quantitative data are provided with this paper. Proteomic dataset is available in PRIDE (project PXD068764): https://www.ebi.ac.uk/pride/archive/projects/PXD068764. The imaging data that support the findings of this study are available from the corresponding author upon reasonable request. Source data are provided with this paper.
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Acknowledgements
We thank Prof Li-Lin Du (NIBS, Beijing, China) for the Pil1 plasmids, Dr Serge Pelet (UNIL, Lausanne, Switzerland) for dPSTR reagents, Dr Manfredo Quadroni (UNIL, Lausanne, Switzerland) and the UNIL Protein Analysis Facility for mass spectrometry, Dr Yoel Klug (Oxford University, UK) for the membrane extraction protocol, Prof Aleksandar Vještica (UNIL, Lausanne, Switzerland) for strains and comments on the manuscript and Prof Omaya Dudin (UNIGE, Geneva, Switzerland), Dr Fangfang Lu (Broad Institute, Cambridge, United States) and members of the Martin lab for comments on the manuscript. This work was supported by grants from the Swiss National Science Foundation (#176396 and # 191990) and the European Research Council (SexYeast) to S.G.M.
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Conceptualisation, B.S. and S.G.M.; methodology, B.S. and L.Me.(Laura Merlini); validation, B.S., L.Me., M.B., W. Li and M.B.; software: W.L.; formal analysis, B.S., L.Me. and W.L.; investigation, B.S., L.Me. and M.B.; resources, L.Mi.(Laetitia Michon), S.G-L.; writing—original draft, B.S.; writing—review and editing, B.S., L.Me. and S.G.M.; visualisation, B.S.; supervision, S.G.M.; funding acquisition, S.G.M.; project administration, B.S. and S.G.M.
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Sieber, B., Merlini, L., Li, W. et al. Phosphoregulation of the novel hemi-arrestin MAPK scaffold Sms1 prevents untimely mating. Nat Commun (2026). https://doi.org/10.1038/s41467-026-70631-9
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DOI: https://doi.org/10.1038/s41467-026-70631-9
