{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T21:11:04Z","timestamp":1790284264105,"version":"4.1.0"},"reference-count":51,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2024,9,24]],"date-time":"2024-09-24T00:00:00Z","timestamp":1727136000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH\/NEI","award":["EY029427"],"award-info":[{"award-number":["EY029427"]}]},{"name":"Ohio Lions Eye Research Foundation","award":["EY029427"],"award-info":[{"award-number":["EY029427"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The synthetic peptide of lumican C-terminal 13 amino acids with the cysteine replaced by an alanine, hereafter referred to as lumikine (LumC13C-A: YEALRVANEVTLN), binds to TGF\u03b2 type I receptor\/activin-like kinase5 (TBR1\/ALK5) in the activated TGF\u03b2 receptor complex to promote corneal epithelial wound healing. The present study aimed to identify the minimum essential amino acid epitope necessary to exert the effects of lumikine via ALK5 and to determine the role of the Y (tyrosine) residue for promoting corneal epithelium wound healing. This study also aimed to determine the signaling pathway(s) triggered by lumican\u2013ALK5 binding. For such, adult Lum knockout (Lum\u2212\/\u2212) mice (~8\u201312 weeks old) were subjected to corneal epithelium debridement using an Agerbrush\u00ae. The injured eyes were treated with 10 \u00b5L eye drops containing 0.3 \u00b5M synthetic peptides designed based on the C-terminal region of lumican for 5\u20136 h. To unveil the downstream signaling pathways involved, inhibitors of the Alk5 and EGFR signaling pathways were co-administered or not. Corneas isolated from the experimental mice were subjected to whole-mount staining and imaged under a ZEISS Observer to determine the distance of epithelium migration. The expression of EGFR ligands was determined following a scratch assay with HTCE (human telomerase-immortalized cornea epithelial cells) in the presence or not of lumikine. Results indicated that shorter LumC-terminal peptides containing EVTLN and substitution of Y with F in lumikine abolishes its capability to promote epithelium migration indicating that Y and EVTLN are essential but insufficient for Lum activity. Lumikine activity is blocked by inhibitors of Alk5, EGFR, and MAPK signaling pathways, while EGF activity is only suppressed by EGFR and MAPK inhibitors. qRT-PCR of scratched HTCE cells cultures treated with lumikine showed upregulated expression of several EGFR ligands including epiregulin (EREG). Treatment with anti-EREG antibodies abolished the effects of lumikine in corneal epithelium debridement healing. The observations suggest that Lum\/lumikine binds Alk5 and promotes the noncanonical Smad-independent TGF\u03b2\/TBRs signaling pathways during the healing of corneal epithelium debridement.<\/jats:p>","DOI":"10.3390\/cells13191599","type":"journal-article","created":{"date-parts":[[2024,9,24]],"date-time":"2024-09-24T03:49:46Z","timestamp":1727149786000},"page":"1599","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Lumican\/Lumikine Promotes Healing of Corneal Epithelium Debridement by Upregulation of EGFR Ligand Expression via Noncanonical Smad-Independent TGF\u03b2\/TBRs Signaling"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8502-0531","authenticated-orcid":false,"given":"Winston W. Y.","family":"Kao","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, University of Cincinnati, Cincinnati, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianhua","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Cincinnati, Cincinnati, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jhuwala","family":"Venkatakrishnan","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Cincinnati, Cincinnati, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4136-7928","authenticated-orcid":false,"given":"Shao-Hsuan","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Cincinnati, Cincinnati, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Cincinnati, Cincinnati, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osamu","family":"Yamanaka","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Cincinnati, Cincinnati, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Cincinnati, Cincinnati, OH 45267, USA"},{"name":"Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0136-0986","authenticated-orcid":false,"given":"Tarsis F.","family":"Gesteira","sequence":"additional","affiliation":[{"name":"College of Optometry, University of Houston, Houston, TX 77204, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2891-1987","authenticated-orcid":false,"given":"Sudhir","family":"Verma","sequence":"additional","affiliation":[{"name":"College of Optometry, University of Houston, Houston, TX 77204, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5848-0225","authenticated-orcid":false,"given":"Vivien J.","family":"Coulson-Thomas","sequence":"additional","affiliation":[{"name":"College of Optometry, University of Houston, Houston, TX 77204, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Yang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, University of Cincinnati, Cincinnati, OH 45267, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4007","DOI":"10.1016\/j.cell.2023.07.036","article-title":"TGF-\u03b2 signaling in health and disease","volume":"186","author":"Sheppard","year":"2023","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Ogata, F.T., Verma, S., Coulson-Thomas, V.J., and Gesteira, T.F. 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