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We have previously shown that epidermal deficiency of a disintegrin and metalloproteinase 17 (ADAM17), the principal EGFR ligand sheddase, results in postnatal skin barrier defects in mice due to impeded TG activity. However, the mechanism by which ADAM17\/EGFR signalling maintains TG activity during epidermal differentiation remains elusive. Here we demonstrate that ADAM17-dependent EGFR signalling promotes TG activity in keratinocytes committed to terminal differentiation by direct induction of TG1 expression. Restored TG1 expression of EGF-stimulated differentiated <jats:italic>Adam17<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> keratinocytes was strongly repressed by inhibitors for PLC\u03b31 or protein kinase C (PKC) pathways, while treatment with the PKC stimulator 12-<jats:italic>O<\/jats:italic>-tetradecanoylphorbol-13-acetate restored TG activity in the epidermis of keratinocyte-specific <jats:italic>Adam17<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> (<jats:italic>AD17<\/jats:italic><jats:sup>\u0394<jats:italic>KC<\/jats:italic><\/jats:sup>) mice. Further investigations emphasized the expression of PKC\u03b7, a mediator of <jats:italic>TGM1<\/jats:italic> transcription, to be sensitive to EGFR activation. In agreement, topical skin application of cholesterol sulfate, an activator of PKC\u03b7, significantly improved TG activity in epidermis of <jats:italic>AD17<\/jats:italic><jats:sup>\u0394<jats:italic>KC<\/jats:italic><\/jats:sup> mice. Our results suggest ADAM17\/EGFR-driven PLC\u03b31 and PKC pathways as important promoters of TG1 expression during terminal keratinocyte differentiation. These findings may help to identify new therapeutic targets for inflammatory skin diseases related to epidermal barrier defects.<\/jats:p>","DOI":"10.1038\/srep39780","type":"journal-article","created":{"date-parts":[[2016,12,22]],"date-time":"2016-12-22T12:37:32Z","timestamp":1482410252000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["ADAM17\/EGFR axis promotes transglutaminase-dependent skin barrier formation through phospholipase C \u03b31 and protein kinase C pathways"],"prefix":"10.1038","volume":"6","author":[{"given":"Cristina","family":"Wolf","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yawen","family":"Qian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew A.","family":"Brooke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David P.","family":"Kelsell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claus-Werner","family":"Franzke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2016,12,22]]},"reference":[{"key":"BFsrep39780_CR1","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1111\/j.1600-0625.2008.00786.x","volume":"17","author":"E Proksch","year":"2008","unstructured":"Proksch, E., Brandner, J. 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