[{"day":"01","month":"08","quality_controlled":"1","oa_version":"Published Version","scopus_import":"1","OA_type":"hybrid","issue":"15","date_updated":"2025-11-27T14:12:24Z","citation":{"mla":"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>.","chicago":"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>.","ieee":"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.","ama":"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>","short":"Y. Jikko, E. Deguchi, K. Matsuda, N. Hino, S. Tsukiji, M. Matsuda, K. Terai, Journal of Cell Science 138 (2025).","ista":"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.","apa":"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>"},"publisher":"The Company of Biologists","department":[{"_id":"CaHe"}],"isi":1,"publication_identifier":{"eissn":["1477-9137"],"issn":[" 0021-9533"]},"status":"public","author":[{"full_name":"Jikko, Yuya","last_name":"Jikko","first_name":"Yuya"},{"first_name":"Eriko","full_name":"Deguchi, Eriko","last_name":"Deguchi"},{"last_name":"Matsuda","full_name":"Matsuda, Kimiya","first_name":"Kimiya"},{"last_name":"Hino","id":"5299a9ce-7679-11eb-a7bc-d1e62b936307","full_name":"Hino, Naoya","first_name":"Naoya"},{"last_name":"Tsukiji","full_name":"Tsukiji, Shinya","first_name":"Shinya"},{"last_name":"Matsuda","full_name":"Matsuda, Michiyuki","first_name":"Michiyuki"},{"first_name":"Kenta","full_name":"Terai, Kenta","last_name":"Terai"}],"pmid":1,"external_id":{"isi":["001567723900009"],"pmid":["40667649"]},"has_accepted_license":"1","article_processing_charge":"Yes (via OA deal)","tmp":{"short":"CC BY (4.0)","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"volume":138,"date_published":"2025-08-01T00:00:00Z","OA_place":"publisher","article_number":"263779","publication_status":"published","article_type":"original","oa":1,"file":[{"access_level":"open_access","file_size":12393297,"success":1,"relation":"main_file","file_id":"20262","creator":"dernst","date_updated":"2025-09-01T10:02:24Z","date_created":"2025-09-01T10:02:24Z","checksum":"29f42619dab5ce251a20c769ed4581c0","content_type":"application/pdf","file_name":"2025_JourCellScience_Jikko.pdf"}],"title":"Front-biased activation of the Ras-Rab5-Rac1 loop coordinates collective cell migration","abstract":[{"lang":"eng","text":"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."}],"file_date_updated":"2025-09-01T10:02:24Z","PlanS_conform":"1","license":"https://creativecommons.org/licenses/by/4.0/","type":"journal_article","acknowledgement":"We are grateful to the members of the Matsuda Laboratory for their helpful input, to K. Hirano, T. Uesugi and K. Takakura, who provided technical assistance, and to the Medical Research Support Center of Kyoto University for DNA sequence analysis. This work was supported by the Kyoto University Live Imaging Center. Financial support was provided by Japan Society for the Promotion of Science (JSPS) KAKENHI grants (21H05226 to K.T., 19H00993 and 20H05898 to M.M.), a Japan Science and Technology Agency (JST) CREST grant (JPMJCR1654 to M.M.), and a JST Moonshot Research and Development Program grant (JPMJPS2022 to M.M.). Open Access funding provided by Tokushima University. Deposited in PMC for immediate release.","publication":"Journal of Cell Science","doi":"10.1242/jcs.263779","ddc":["570"],"intvolume":"       138","_id":"20188","date_created":"2025-08-17T22:01:36Z","language":[{"iso":"eng"}],"user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","year":"2025"},{"publication":"Current Biology","type":"journal_article","_id":"18651","doi":"10.1016/j.cub.2024.10.065","intvolume":"        34","date_created":"2024-12-15T23:01:49Z","language":[{"iso":"eng"}],"year":"2024","user_id":"317138e5-6ab7-11ef-aa6d-ffef3953e345","article_type":"letter_note","publication_status":"published","title":"Development: Turing mechanics","page":"R1230-R1232","abstract":[{"lang":"eng","text":"Embryo axis formation begins with the localized expression of biochemical signals, which organize cell movements and determine cell fate. A quail study finds that tissue contraction and resulting long-range changes in tissue tension restrict the area where these biochemical signals are expressed."}],"department":[{"_id":"CaHe"}],"corr_author":"1","date_updated":"2025-09-09T11:51:15Z","publisher":"Elsevier","citation":{"ama":"Hino N, Santos Fernandes Lasbarrères Camelo C, Heisenberg C-PJ. Development: Turing mechanics. <i>Current Biology</i>. 2024;34(24):R1230-R1232. doi:<a href=\"https://doi.org/10.1016/j.cub.2024.10.065\">10.1016/j.cub.2024.10.065</a>","ieee":"N. Hino, C. Santos Fernandes Lasbarrères Camelo, and C.-P. J. Heisenberg, “Development: Turing mechanics,” <i>Current Biology</i>, vol. 34, no. 24. Elsevier, pp. R1230–R1232, 2024.","chicago":"Hino, Naoya, Carolina Santos Fernandes Lasbarrères Camelo, and Carl-Philipp J Heisenberg. “Development: Turing Mechanics.” <i>Current Biology</i>. Elsevier, 2024. <a href=\"https://doi.org/10.1016/j.cub.2024.10.065\">https://doi.org/10.1016/j.cub.2024.10.065</a>.","mla":"Hino, Naoya, et al. “Development: Turing Mechanics.” <i>Current Biology</i>, vol. 34, no. 24, Elsevier, 2024, pp. R1230–32, doi:<a href=\"https://doi.org/10.1016/j.cub.2024.10.065\">10.1016/j.cub.2024.10.065</a>.","apa":"Hino, N., Santos Fernandes Lasbarrères Camelo, C., &#38; Heisenberg, C.-P. J. (2024). Development: Turing mechanics. <i>Current Biology</i>. Elsevier. <a href=\"https://doi.org/10.1016/j.cub.2024.10.065\">https://doi.org/10.1016/j.cub.2024.10.065</a>","ista":"Hino N, Santos Fernandes Lasbarrères Camelo C, Heisenberg C-PJ. 2024. Development: Turing mechanics. Current Biology. 34(24), R1230–R1232.","short":"N. Hino, C. Santos Fernandes Lasbarrères Camelo, C.-P.J. Heisenberg, Current Biology 34 (2024) R1230–R1232."},"status":"public","publication_identifier":{"issn":["0960-9822"],"eissn":["1879-0445"]},"isi":1,"article_processing_charge":"No","external_id":{"isi":["001392077000001"],"pmid":["39689690"]},"author":[{"id":"5299a9ce-7679-11eb-a7bc-d1e62b936307","full_name":"Hino, Naoya","last_name":"Hino","first_name":"Naoya"},{"last_name":"Santos Fernandes Lasbarrères Camelo","id":"6347dca5-074c-11ed-af92-a80f860d9d5b","full_name":"Santos Fernandes Lasbarrères Camelo, Carolina","first_name":"Carolina"},{"id":"39427864-F248-11E8-B48F-1D18A9856A87","full_name":"Heisenberg, Carl-Philipp J","orcid":"0000-0002-0912-4566","last_name":"Heisenberg","first_name":"Carl-Philipp J"}],"pmid":1,"volume":34,"date_published":"2024-12-16T00:00:00Z","day":"16","month":"12","scopus_import":"1","OA_type":"closed access","oa_version":"None","quality_controlled":"1","issue":"24"},{"article_number":"102217","article_type":"review","publication_status":"published","oa":1,"title":"Stretching the limits of extracellular signal-related kinase (ERK) signaling — Cell mechanosensing to ERK activation","file":[{"date_created":"2024-01-30T12:52:12Z","content_type":"application/pdf","checksum":"25923f8ae71344e8974530dd23c71bdc","file_name":"2023_CurrentOpinionCellBio_Hirashima.pdf","file_size":1173762,"access_level":"open_access","success":1,"relation":"main_file","file_id":"14909","date_updated":"2024-01-30T12:52:12Z","creator":"dernst"}],"abstract":[{"text":"Extracellular signal-regulated kinase (ERK) has been recognized as a critical regulator in various physiological and pathological processes. Extensive research has elucidated the signaling mechanisms governing ERK activation via biochemical regulations with upstream molecules, particularly receptor tyrosine kinases (RTKs). However, recent advances have highlighted the role of mechanical forces in activating the RTK–ERK signaling pathways, thereby opening new avenues of research into mechanochemical interplay in multicellular tissues. Here, we review the force-induced ERK activation in cells and propose possible mechanosensing mechanisms underlying the mechanoresponsive ERK activation. We conclude that mechanical forces are not merely passive factors shaping cells and tissues but also active regulators of cellular signaling pathways controlling collective cell behaviors.","lang":"eng"}],"file_date_updated":"2024-01-30T12:52:12Z","type":"journal_article","acknowledgement":"TH was supported by JSPS KAKENHI Grant (no. 21H05290) and the Ministry of Education under the Research Centres of Excellence programme through the Mechanobiology Institute at National University of Singapore and by Department of Physiology at National University of Singapore. NH was supported by JSPS KAKENHI Grant (no. 20K22653). KA was supported by JSPS KAKENHI Grants (no. 19H05798 and no. 22H02625). MM was supported by JSPS KAKENHI Grants (no. 19H00993 and no. 20H05898) and JST Moonshot R&D Grant JPMJPS2022. We appreciate Virgile Viasnoff and the lab members for their valuable comments on the manuscript. We apologize to authors whose work could not be highlighted due to space limitations.","publication":"Current Opinion in Cell Biology","ddc":["570"],"doi":"10.1016/j.ceb.2023.102217","intvolume":"        84","_id":"14080","language":[{"iso":"eng"}],"date_created":"2023-08-20T22:01:12Z","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","year":"2023","day":"01","month":"10","quality_controlled":"1","oa_version":"Published Version","scopus_import":"1","issue":"10","date_updated":"2024-01-30T12:52:42Z","publisher":"Elsevier","citation":{"short":"T. Hirashima, N. Hino, K. Aoki, M. Matsuda, Current Opinion in Cell Biology 84 (2023).","apa":"Hirashima, T., Hino, N., Aoki, K., &#38; Matsuda, M. (2023). Stretching the limits of extracellular signal-related kinase (ERK) signaling — Cell mechanosensing to ERK activation. <i>Current Opinion in Cell Biology</i>. Elsevier. <a href=\"https://doi.org/10.1016/j.ceb.2023.102217\">https://doi.org/10.1016/j.ceb.2023.102217</a>","ista":"Hirashima T, Hino N, Aoki K, Matsuda M. 2023. Stretching the limits of extracellular signal-related kinase (ERK) signaling — Cell mechanosensing to ERK activation. Current Opinion in Cell Biology. 84(10), 102217.","ieee":"T. Hirashima, N. Hino, K. Aoki, and M. Matsuda, “Stretching the limits of extracellular signal-related kinase (ERK) signaling — Cell mechanosensing to ERK activation,” <i>Current Opinion in Cell Biology</i>, vol. 84, no. 10. Elsevier, 2023.","mla":"Hirashima, Tsuyoshi, et al. “Stretching the Limits of Extracellular Signal-Related Kinase (ERK) Signaling — Cell Mechanosensing to ERK Activation.” <i>Current Opinion in Cell Biology</i>, vol. 84, no. 10, 102217, Elsevier, 2023, doi:<a href=\"https://doi.org/10.1016/j.ceb.2023.102217\">10.1016/j.ceb.2023.102217</a>.","chicago":"Hirashima, Tsuyoshi, Naoya Hino, Kazuhiro Aoki, and Michiyuki Matsuda. “Stretching the Limits of Extracellular Signal-Related Kinase (ERK) Signaling — Cell Mechanosensing to ERK Activation.” <i>Current Opinion in Cell Biology</i>. Elsevier, 2023. <a href=\"https://doi.org/10.1016/j.ceb.2023.102217\">https://doi.org/10.1016/j.ceb.2023.102217</a>.","ama":"Hirashima T, Hino N, Aoki K, Matsuda M. Stretching the limits of extracellular signal-related kinase (ERK) signaling — Cell mechanosensing to ERK activation. <i>Current Opinion in Cell Biology</i>. 2023;84(10). doi:<a href=\"https://doi.org/10.1016/j.ceb.2023.102217\">10.1016/j.ceb.2023.102217</a>"},"department":[{"_id":"CaHe"}],"publication_identifier":{"eissn":["1879-0410"],"issn":["0955-0674"]},"isi":1,"status":"public","author":[{"first_name":"Tsuyoshi","full_name":"Hirashima, Tsuyoshi","last_name":"Hirashima"},{"last_name":"Hino","id":"5299a9ce-7679-11eb-a7bc-d1e62b936307","full_name":"Hino, Naoya","first_name":"Naoya"},{"last_name":"Aoki","full_name":"Aoki, Kazuhiro","first_name":"Kazuhiro"},{"full_name":"Matsuda, Michiyuki","last_name":"Matsuda","first_name":"Michiyuki"}],"pmid":1,"external_id":{"isi":["001054692200001"],"pmid":["37574635"]},"has_accepted_license":"1","article_processing_charge":"Yes (in subscription journal)","tmp":{"short":"CC BY (4.0)","image":"/images/cc_by.png","name":"Creative Commons Attribution 4.0 International Public License (CC-BY 4.0)","legal_code_url":"https://creativecommons.org/licenses/by/4.0/legalcode"},"volume":84,"date_published":"2023-10-01T00:00:00Z"},{"month":"10","keyword":["Developmental Biology","Cell Biology","General Biochemistry","Genetics and Molecular Biology","Molecular Biology"],"day":"01","issue":"19","quality_controlled":"1","scopus_import":"1","oa_version":"Published Version","OA_type":"free access","publication_identifier":{"issn":["1534-5807"]},"isi":1,"status":"public","date_updated":"2025-06-25T07:35:27Z","publisher":"Elsevier","citation":{"ama":"Hino N, Matsuda K, Jikko Y, et al. A feedback loop between lamellipodial extension and HGF-ERK signaling specifies leader cells during collective cell migration. <i>Developmental Cell</i>. 2022;57(19):2290-2304.e7. doi:<a href=\"https://doi.org/10.1016/j.devcel.2022.09.003\">10.1016/j.devcel.2022.09.003</a>","ieee":"N. Hino <i>et al.</i>, “A feedback loop between lamellipodial extension and HGF-ERK signaling specifies leader cells during collective cell migration,” <i>Developmental Cell</i>, vol. 57, no. 19. Elsevier, p. 2290–2304.e7, 2022.","chicago":"Hino, Naoya, Kimiya Matsuda, Yuya Jikko, Gembu Maryu, Katsuya Sakai, Ryu Imamura, Shinya Tsukiji, et al. “A Feedback Loop between Lamellipodial Extension and HGF-ERK Signaling Specifies Leader Cells during Collective Cell Migration.” <i>Developmental Cell</i>. Elsevier, 2022. <a href=\"https://doi.org/10.1016/j.devcel.2022.09.003\">https://doi.org/10.1016/j.devcel.2022.09.003</a>.","mla":"Hino, Naoya, et al. “A Feedback Loop between Lamellipodial Extension and HGF-ERK Signaling Specifies Leader Cells during Collective Cell Migration.” <i>Developmental Cell</i>, vol. 57, no. 19, Elsevier, 2022, p. 2290–2304.e7, doi:<a href=\"https://doi.org/10.1016/j.devcel.2022.09.003\">10.1016/j.devcel.2022.09.003</a>.","apa":"Hino, N., Matsuda, K., Jikko, Y., Maryu, G., Sakai, K., Imamura, R., … Matsuda, M. (2022). A feedback loop between lamellipodial extension and HGF-ERK signaling specifies leader cells during collective cell migration. <i>Developmental Cell</i>. Elsevier. <a href=\"https://doi.org/10.1016/j.devcel.2022.09.003\">https://doi.org/10.1016/j.devcel.2022.09.003</a>","ista":"Hino N, Matsuda K, Jikko Y, Maryu G, Sakai K, Imamura R, Tsukiji S, Aoki K, Terai K, Hirashima T, Trepat X, Matsuda M. 2022. A feedback loop between lamellipodial extension and HGF-ERK signaling specifies leader cells during collective cell migration. Developmental Cell. 57(19), 2290–2304.e7.","short":"N. Hino, K. Matsuda, Y. Jikko, G. Maryu, K. Sakai, R. Imamura, S. Tsukiji, K. Aoki, K. Terai, T. Hirashima, X. Trepat, M. Matsuda, Developmental Cell 57 (2022) 2290–2304.e7."},"department":[{"_id":"CaHe"}],"corr_author":"1","date_published":"2022-10-01T00:00:00Z","volume":57,"OA_place":"publisher","author":[{"last_name":"Hino","full_name":"Hino, Naoya","id":"5299a9ce-7679-11eb-a7bc-d1e62b936307","first_name":"Naoya"},{"full_name":"Matsuda, Kimiya","last_name":"Matsuda","first_name":"Kimiya"},{"last_name":"Jikko","full_name":"Jikko, Yuya","first_name":"Yuya"},{"last_name":"Maryu","full_name":"Maryu, Gembu","first_name":"Gembu"},{"first_name":"Katsuya","full_name":"Sakai, Katsuya","last_name":"Sakai"},{"first_name":"Ryu","last_name":"Imamura","full_name":"Imamura, Ryu"},{"full_name":"Tsukiji, Shinya","last_name":"Tsukiji","first_name":"Shinya"},{"first_name":"Kazuhiro","full_name":"Aoki, Kazuhiro","last_name":"Aoki"},{"first_name":"Kenta","full_name":"Terai, Kenta","last_name":"Terai"},{"last_name":"Hirashima","full_name":"Hirashima, Tsuyoshi","first_name":"Tsuyoshi"},{"first_name":"Xavier","full_name":"Trepat, Xavier","last_name":"Trepat"},{"first_name":"Michiyuki","last_name":"Matsuda","full_name":"Matsuda, Michiyuki"}],"pmid":1,"article_processing_charge":"No","external_id":{"isi":["000898428700006"],"pmid":["36174555"]},"title":"A feedback loop between lamellipodial extension and HGF-ERK signaling specifies leader cells during collective cell migration","page":"2290-2304.e7","article_type":"original","publication_status":"published","oa":1,"main_file_link":[{"url":"https://doi.org/10.1016/j.devcel.2022.09.003","open_access":"1"}],"abstract":[{"lang":"eng","text":"Upon the initiation of collective cell migration, the cells at the free edge are specified as leader cells; however, the mechanism underlying the leader cell specification remains elusive. Here, we show that lamellipodial extension after the release from mechanical confinement causes sustained extracellular signal-regulated kinase (ERK) activation and underlies the leader cell specification. Live-imaging of Madin-Darby canine kidney (MDCK) cells and mouse epidermis through the use of Förster resonance energy transfer (FRET)-based biosensors showed that leader cells exhibit sustained ERK activation in a hepatocyte growth factor (HGF)-dependent manner. Meanwhile, follower cells exhibit oscillatory ERK activation waves in an epidermal growth factor (EGF) signaling-dependent manner. Lamellipodial extension at the free edge increases the cellular sensitivity to HGF. The HGF-dependent ERK activation, in turn, promotes lamellipodial extension, thereby forming a positive feedback loop between cell extension and ERK activation and specifying the cells at the free edge as the leader cells. Our findings show that the integration of physical and biochemical cues underlies the leader cell specification during collective cell migration."}],"acknowledgement":"We thank the members of the Matsuda Laboratory for their helpful discussion and encouragement, and we thank K. Hirano and K. Takakura for their technical assistance. This work was supported by the Kyoto University Live Imaging Center. Financial support was provided in the form of JSPS KAKENHI grants (nos. 17J02107 and 20K22653 to N.H., and 20H05898 and 19H00993 to M.M.), a JST CREST grant (no. JPMJCR1654 to M.M.), a Moonshot R&D grant (no. JPMJPS2022-11 to M.M.), Generalitat de Catalunya and the CERCA Programme (no. SGR-2017-01602 to X.T.), MICCINN/FEDER (no. PGC2018-099645-B-I00 to X.T.), and European Research Council (no. Adv-883739 to X.T.). IBEC is a recipient of a Severo Ochoa Award of Excellence from the MINECO. This work was partly supported by an Extramural Collaborative Research Grant of Cancer Research Institute, Kanazawa University.","type":"journal_article","publication":"Developmental Cell","date_created":"2023-01-16T09:51:39Z","language":[{"iso":"eng"}],"year":"2022","user_id":"2DF688A6-F248-11E8-B48F-1D18A9856A87","doi":"10.1016/j.devcel.2022.09.003","intvolume":"        57","_id":"12238"}]