article published yes Yuya Jikko author Eriko Deguchi author Kimiya Matsuda author Naoya Hino author 5299a9ce-7679-11eb-a7bc-d1e62b936307 Shinya Tsukiji author Michiyuki Matsuda author Kenta Terai author CaHe department Collective cell migration is coordinated by the front-to-rear intercellular propagation of EGFR-Ras-ERK pathway activation. However, the molecular mechanisms integrating front-to-rear information into this intercellular signaling cascade, particularly the determinants of cellular front-side specification, remain elusive. We visualized the activity of EGFR, Ras, Rac1 and Rab5A (hereafter Rab5) by using FRET biosensors and chemogenetic tools. Whereas EGFR activation was uniformly observed within cells, Ras activation was biased to the front side within cells. The polarized Ras activation depended on Merlin and Rac1, which also showed front-biased activation. Furthermore, Rab5, a crucial regulator of cell migration, demonstrated similar front-biased activation and was found to function downstream of Ras while being necessary for Rac1 activation. Thus, the positive feedback loop consisting of Ras, Rab5 and Rac1 is activated primarily at the front of collectively migrating cells. These findings offer new spatio-temporal insight into processing front–rear information during collective cell migration. https://research-explorer.ista.ac.at/download/20188/20262/2025_JourCellScience_Jikko.pdf application/pdfno https://creativecommons.org/licenses/by/4.0/ The Company of Biologists2025 eng 0021-9533 1477-9137 40667649 00156772390000910.1242/jcs.263779 13815 Jikko Y, Deguchi E, Matsuda K, et al. Front-biased activation of the Ras-Rab5-Rac1 loop coordinates collective cell migration. <i>Journal of Cell Science</i>. 2025;138(15). doi:<a href="https://doi.org/10.1242/jcs.263779">10.1242/jcs.263779</a> Jikko, Yuya, Eriko Deguchi, Kimiya Matsuda, Naoya Hino, Shinya Tsukiji, Michiyuki Matsuda, and Kenta Terai. “Front-Biased Activation of the Ras-Rab5-Rac1 Loop Coordinates Collective Cell Migration.” <i>Journal of Cell Science</i>. The Company of Biologists, 2025. <a href="https://doi.org/10.1242/jcs.263779">https://doi.org/10.1242/jcs.263779</a>. Y. Jikko, E. Deguchi, K. Matsuda, N. Hino, S. Tsukiji, M. Matsuda, K. Terai, Journal of Cell Science 138 (2025). Jikko, Yuya, et al. “Front-Biased Activation of the Ras-Rab5-Rac1 Loop Coordinates Collective Cell Migration.” <i>Journal of Cell Science</i>, vol. 138, no. 15, 263779, The Company of Biologists, 2025, doi:<a href="https://doi.org/10.1242/jcs.263779">10.1242/jcs.263779</a>. Y. Jikko <i>et al.</i>, “Front-biased activation of the Ras-Rab5-Rac1 loop coordinates collective cell migration,” <i>Journal of Cell Science</i>, vol. 138, no. 15. The Company of Biologists, 2025. Jikko, Y., Deguchi, E., Matsuda, K., Hino, N., Tsukiji, S., Matsuda, M., &#38; Terai, K. (2025). Front-biased activation of the Ras-Rab5-Rac1 loop coordinates collective cell migration. <i>Journal of Cell Science</i>. The Company of Biologists. <a href="https://doi.org/10.1242/jcs.263779">https://doi.org/10.1242/jcs.263779</a> Jikko Y, Deguchi E, Matsuda K, Hino N, Tsukiji S, Matsuda M, Terai K. 2025. Front-biased activation of the Ras-Rab5-Rac1 loop coordinates collective cell migration. Journal of Cell Science. 138(15), 263779. 201882025-08-17T22:01:36Z2025-11-27T14:12:24Z