| First Author | Wolf C | Year | 2016 |
| Journal | Sci Rep | Volume | 6 |
| Pages | 39780 | PubMed ID | 28004780 |
| Mgi Jnum | J:253846 | Mgi Id | MGI:6102460 |
| Doi | 10.1038/srep39780 | Citation | Wolf C, et al. (2016) ADAM17/EGFR axis promotes transglutaminase-dependent skin barrier formation through phosholipase C gamma1 and protein kinase C pathways. Sci Rep 6:39780 |
| abstractText | The vitally important skin barrier is formed by extensive cross-linking activity of transglutaminases (TGs) during terminal epidermal differentiation. 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 Adam17(-/-) keratinocytes was strongly repressed by inhibitors for PLCgamma1 or protein kinase C (PKC) pathways, while treatment with the PKC stimulator 12-O-tetradecanoylphorbol-13-acetate restored TG activity in the epidermis of keratinocyte-specific Adam17(-/-) (AD17(DeltaKC)) mice. Further investigations emphasized the expression of PKCeta, a mediator of TGM1 transcription, to be sensitive to EGFR activation. In agreement, topical skin application of cholesterol sulfate, an activator of PKCeta, significantly improved TG activity in epidermis of AD17(DeltaKC) mice. Our results suggest ADAM17/EGFR-driven PLCgamma1 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. |
