Abstract
Kinase-mediated phosphorylation is crucial for thermal adaptation. While extracellular signal-regulated kinase 1/2 (ERK1/2) signaling is well characterized in model organisms, its functional divergence and genetic regulation in marine species with distinct thermal adaptations remain poorly understood. In this study, we investigated the genetic basis of differential ERK activation under heat stress using two oyster subspecies from distinct thermal niches: Crassostrea gigas and Crassostrea angulata. Combining ERK inhibition assays with heat stress treatments, followed by proteomic and phosphoproteomic profiling, we constructed a heat-responsive ERK network and identified that ERK phosphorylates ATP-dependent 6-phosphofructokinase (PFK) at Thr775, enhancing its enzymatic activity and glycolytic capacity. Genome-wide association analysis further revealed that a synonymous mutation in the leucine-rich repeat protein SHOC2 drives divergent ERK phosphorylation patterns between the two subspecies by altering RNA structure and expression. Our findings demonstrated that the heat-responsive SHOC2-BRAF-ERK-PFK cascade exhibits stronger activation in thermotolerant species, enabling marine ectotherms to fine-tune metabolic responses to temperature variation. This study serves as an experimental case elucidating how genetic variations shape thermal adaptation divergence through phosphorylation-mediated regulation, thereby providing a molecular framework for adaptive mechanisms of climate variability.
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Data availability
The proteome and phosphoproteome data have been uploaded in ProteomeXchange Consortium under the accession numbers PXD065668 and PXD065706. The raw sequencing data of AG × AG hybrid F2 population in this study are available in the Sequence Read Archive (SRA) BioProject under the accession number: PRJNA1255741 (https://doi.org/10.1016/j.ijbiomac.2025.145808)114. The raw sequencing data of Crassostrea gigas and Crassostrea angulata are available in the GigaScience GigaDB database (https://doi.org/10.1093/gigascience/giad077)44. Additionally, all numerical source data for charts/graphs have been provided in the Supplementary Data 5. All uncropped blot images of Western blots presented in this study are presented in Supplementary Figs. 12–19.
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Acknowledgements
The authors thank the supercomputer cluster of the High Performance Computing Center (HPCC) at the Institute of Oceanology, Chinese Academy of Sciences for support in bioinformatics analysis. This research was funded by the National Key R&D Program of China (no. 2022YFD2400304), Key Research and Development Program of Shandong (ZFJH202309 and 2025TZXD030), the National Natural Science Foundation of China (no. 32101353), the Key Research and Development Program of Shandong (2024LZGCQY003), the Department of Science & Technology of Shandong Province (2022GJJLJRC02-096), and China Agriculture Research System of MOF and MARA (no. CARS-49).
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L.L., G.Z. conceived the study. M.W., C.W. carried out the field and laboratory work, collected the oyster samples, participated in the data analysis, and drafted the manuscript. M.D., Z.J., J.C., M.P., T.Z., R.C. and W.W. contributed to cultural management. C.W., L.L. and G.Z. revised the manuscript. All authors approved the manuscript for publication.
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Wang, M., Wang, C., Du, M. et al. A naturally synonymous mutation modulates an ERK-centered regulatory network to mediate thermotolerance divergence in Crassostrea oysters. Commun Biol (2026). https://doi.org/10.1038/s42003-026-10054-w
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DOI: https://doi.org/10.1038/s42003-026-10054-w
