A Naturally Synonymous Mutation in SHOC2 Modulates ERK-PFK Cascade to Mediate Thermotolerance Divergence Among Oysters | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article A Naturally Synonymous Mutation in SHOC2 Modulates ERK-PFK Cascade to Mediate Thermotolerance Divergence Among Oysters Li Li, Min Wang, Chaogang Wang, Mingyang Du, Zhuxiang Jiang, Jincheng Chen, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7424750/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Kinase-mediated phosphorylation modifications play a pivotal role in thermal adaptation. Although extensive research has focused on the signaling transduction pathways of specific kinases, such as ERK, in model organisms, their functions and genetic divergence mechanisms in marine species with differential thermal adaptation remain poorly understood. Here, we employed two closely related oyster species inhabiting distinct thermal niches to investigate the genetic regulatory mechanisms underlying differentially heat-activated ERK kinases. Combining ERK inhibition assays with heat stress, followed by proteomic and phosphoproteomic profiling, we systematically analyzed the downstream regulatory network of ERK kinases in oysters, and then firstly reported that the ERK1/2-mediated phosphorylation at conserved PFK Thr775 enhances its enzymatic activity and glycolytic capacity. Genome-wide association analysis further revealed that a synonymous mutation in the Shoc2 gene drives divergent ERK phosphorylation activated patterns between two oyster species by modulating RNA secondary structure stability and expression levels. Our findings demonstrated that the heat-responsive SHOC2-BRAF-ERK-PFK cascade exhibited stronger activation in thermotolerant species, enabling marine ectotherms to fine-tune metabolic responses to environmental temperature variation. This study serves as an experimental case elucidating how genetic variations shape thermal adaptation divergence through phosphorylation-mediated post-translational regulation, thereby providing a molecular framework for adaptive mechanisms of climate variability. Biological sciences/Genetics/Mutation Biological sciences/Molecular biology/Post-translational modifications Biological sciences/Evolution/Evolutionary genetics ERK1/2 Synonymous mutation Phosphorylation modification Thermal Adaptation Oysters Full Text Additional Declarations There is NO Competing Interest. Supplementary Files TableS1.xlsx The primer sequences used in this study TableS5.xlsx The Vertebrates and invertebrates PFK protein sequences analyzed in this study Supplementaryfigure.pdf Supplemenrary figure TableS2.xlsx The significant differentially abundant proteins (DAPs) regulated by ERK kinases under heat stress. TableS3.xlsx The significant differentially phosphorylated proteins (DPPs) regulated by ERK kinases under heat stress. TableS4.xlsx The functional classification of significantly differentially phosphorylated proteins (DPPs) and differentially abundant proteins (DAPs) mediated by ERK kinase under heat stress Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7424750","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":506923106,"identity":"b6982dd6-06e8-47bc-95e0-15b77877d52f","order_by":0,"name":"Li 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