{"doi":"10.1016/j.celrep.2024.114986","title":"Low-affinity ligands of the epidermal growth factor receptor are long-range signal transmitters in collective cell migration of epithelial cells","abstract":"Canonical epidermal growth factor (EGF) receptor (EGFR) activation involves the binding of seven EGFR ligands (EGFRLs); however, their extracellular dynamics remain elusive. Here, employing fluorescent probes and a tool for triggering ectodomain shedding, we show that epiregulin (EREG), a low-affinity EGFRL, rapidly and efficiently activates EGFR in Madin-Darby canine kidney (MDCK) epithelial cells and mouse epidermis. During collective cell migration, EGFR and extracellular signal-regulated kinase (ERK) activation waves propagate in an a disintegrin and metalloprotease 17 (ADAM17) sheddase- and EGFRL-dependent manner. Upon induced EGFRL shedding, low-affinity ligands EREG and amphiregulin (AREG) mediate faster and broader ERK waves than high-affinity ligands. Tight/adherens junction integrity is essential for ERK activation propagation, suggesting that tight intercellular spaces prefer the low-affinity EGFRLs for efficient signal transmission. In EREG-deficient mice, ERK wave propagation and cell migration were impaired during skin wound repair. We additionally show that heparin-binding EGF-like growth factor (HBEGF) primarily promotes surrounding cell motility. Our findings underscore the pivotal role of low-affinity EGFRLs in rapid intercellular signal transmission. • EGFRL probes visualize the dynamics of individual EGFRLs in the extracellular space • Chemogenetic EGFRL shedding induces ERK activation in surrounding cells • Low-affinity EGFRLs diffuse farther compared to high-affinity ones • EREG plays a role in collective cell migration and skin wound repair in vivo Deguchi et al. find that low-affinity EGFR ligands propagate faster and farther than high-affinity ligands in epithelial cells. They demonstrate that EREG, a low-affinity ligand, contributes to skin wound healing.","journal":"Cell Reports","year":2024,"id":423137,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":25,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9605,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":225436,"name":"Shuhao Lin","orcid":"0000-0002-7982-746X","position":1,"is_corresponding":false},{"id":1218844,"name":"Daiki Hirayama","orcid":null,"position":2,"is_corresponding":false},{"id":1218845,"name":"Kimiya Matsuda","orcid":null,"position":3,"is_corresponding":false},{"id":1218188,"name":"Akira Tanave","orcid":"0009-0006-2832-8069","position":4,"is_corresponding":false},{"id":162128,"name":"Kenta Sumiyama","orcid":"0000-0001-8785-5439","position":5,"is_corresponding":false},{"id":1218189,"name":"Shinya Tsukiji","orcid":"0000-0002-1402-5773","position":6,"is_corresponding":false},{"id":1218190,"name":"Tetsuhisa Otani","orcid":"0000-0002-2557-6722","position":7,"is_corresponding":false},{"id":392384,"name":"Mikio Furuse","orcid":"0000-0003-2847-8156","position":8,"is_corresponding":false},{"id":360777,"name":"Alexander Sorkin","orcid":"0000-0002-4446-1920","position":9,"is_corresponding":false},{"id":357043,"name":"Michiyuki Matsuda","orcid":"0000-0002-5876-9969","position":10,"is_corresponding":false},{"id":357042,"name":"Kenta Terai","orcid":"0000-0001-7638-3720","position":11,"is_corresponding":false},{"id":1218843,"name":"Eriko Deguchi","orcid":null,"position":0,"is_corresponding":true}],"reference_count":76,"raw_metadata":null,"created_at":"2026-07-19T01:57:56.814994Z","pmid":"39546398","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}