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ERK activity is highly dynamic within individual cells and drives cell proliferation, metabolism, and other processes through effector proteins including c-Myc, c-Fos, Fra-1, and Egr-1. These proteins are sensitive to the dynamics of ERK activity, but it is not clear to what extent the pattern of ERK activity in an individual cell determines effector protein expression, or how much information about ERK dynamics is embedded in the pattern of effector expression. Here, we evaluate these relationships using live-cell biosensor measurements of ERK activity, multiplexed with immunofluorescence staining for downstream target proteins of the pathway. Combining these datasets with linear regression, machine learning, and differential equation models, we develop an interpretive framework for immunofluorescence data, wherein Fra-1 and pRb levels imply long-term activation of ERK signaling, while Egr-1 and c-Myc indicate more recent activation. Analysis of multiple cancer cell lines reveals a distorted relationship between ERK activity and cell state in malignant cells. We show that this framework can infer various classes of ERK dynamics from effector protein stains within a heterogeneous population, providing a basis for annotating ERK dynamics within fixed cells.<\/jats:p>","DOI":"10.1038\/s41467-025-58348-7","type":"journal-article","created":{"date-parts":[[2025,5,21]],"date-time":"2025-05-21T09:24:06Z","timestamp":1747819446000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Deciphering the history of ERK activity from fixed-cell immunofluorescence measurements"],"prefix":"10.1038","volume":"16","author":[{"given":"Abhineet","family":"Ram","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Pargett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3241-0042","authenticated-orcid":false,"given":"Yongin","family":"Choi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devan","family":"Murphy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolyn","family":"Teragawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4838-1449","authenticated-orcid":false,"given":"Markhus","family":"Cabel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nont","family":"Kosaisawe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1716-0153","authenticated-orcid":false,"given":"Gerald","family":"Quon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2688-8653","authenticated-orcid":false,"given":"John G.","family":"Albeck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,21]]},"reference":[{"key":"58348_CR1","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1038\/s41580-020-0255-7","volume":"21","author":"H Lavoie","year":"2020","unstructured":"Lavoie, H., Gagnon, J. & Therrien, M. 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The other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All collaborators have fulfilled the criteria for authorship required by Nature Portfolio and are included as authors of this study. This research is locally relevant and included local researchers throughout the entire research process including study design, study implementation, data ownership, intellectual property, and authorship of publications. Roles and responsibilities were agreed amongst collaborators ahead of the research. This research was not severely restricted or prohibited in the researchers\u2019 setting. This work does not result in stigmatization, incrimination, discrimination or otherwise personal risk to participants, nor does it risk the health, safety, and security of the researchers. We have considered relevant local and regional research in the citations.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Inclusion and Ethics"}}],"article-number":"4721"}}