title: ADAM17/EGFR axis promotes transglutaminase-dependent skin barrier formation through phospholipase C γ1 and protein kinase C pathways.
abstract: 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 PLCγ1 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-/-(AD17ΔKC) mice. Further investigations emphasized the expression of PKCη, a mediator of TGM1 transcription, to be sensitive to EGFR activation. In agreement, topical skin application of cholesterol sulfate, an activator of PKCη, significantly improved TG activity in epidermis of AD17ΔKCmice. Our results suggest ADAM17/EGFR-driven PLCγ1 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.
authors.affiliation: Department of Dermatology, Medical Center - University of Freiburg, Freiburg, Germany.
authors.forename: Cristina
authors.initials: C
authors.lastname: Wolf
authors.affiliation: Department of Dermatology, Medical Center - University of Freiburg, Freiburg, Germany.
authors.forename: Yawen
authors.initials: Y
authors.lastname: Qian
authors.affiliation: Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Brooke
authors.affiliation: Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: David P
authors.initials: DP
authors.lastname: Kelsell
authors.affiliation: Department of Dermatology, Medical Center - University of Freiburg, Freiburg, Germany.
authors.forename: Claus-Werner
authors.initials: CW
authors.lastname: Franzke
mesh_terms: D000072198:ADAM17 Protein / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004817:Epidermis / Q000201:enzymology*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D015603:Keratinocytes / Q000201:enzymology*; D051379:Mice; D008822:Mice, Transgenic; D051966:Phospholipase C gamma / Q000235:genetics / Q000378:metabolism*; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D011503:Transglutaminases / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D011503:Transglutaminases; C105804:transglutaminase 1; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D011493:Protein Kinase C; D051966:Phospholipase C gamma; C117399:Plcg1 protein, mouse; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse