This work was supported by the German Research Foundation DFG (SFB 850/B6) and by the Fritz-Thyssen
foundation (Az.10.14.2.150) to C.-W.F and the Medical Research Council (MR/L010402/1) to D.P.K

A Murthy

A Sääf

A Toker

AA Długosz

BM Lichtenberger

CA Strott

CP Blobel

CW Franzke

DC Blaydon

E Candi

E Proksch

E Ueda

EM Hur

F Spörl

G Adhikary

H Wakita

HR Seo

JJ Peschon

JM Haugh

K Chanprapaph

K Chida

K Nishi

L Eckhart

LJ Russell

M Jost

M Kashiwagi

M Ohba

M Piepkorn

M Pigors

M Raghunath

M Sibilia

MA Brooke

MF Denning

MJ Kim

MJ Wieduwilt

MR Schneider

NJ Reynolds

P Campbell

P Gierschik

P Tsukerman

PJ Miettinen

PT La Celle

RA Black

S John

S Kawabe

S Pastore

S Tholen

SS Tibudan

U Sahin

V Mitev

X Cheng

Z Xie

Scientific Reports

PubMed

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 AD17ΔKC mice. 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

Wolf, Cristina

Qian, Yawen

Brooke, Matthew A.

Kelsell, David P.

Franzke, Claus-Werner

FreiDok plus

ADAM17/EGFR axis promotes transglutaminase-dependent skin barrier formation through phospholipase C γ1 and protein kinase C pathways

AbstractThe 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 AD17ΔKC mice. 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.</jats:p

Cristina Wolf

Yawen Qian

Matthew A. Brooke

David P. Kelsell

Claus-Werner Franzke

Crossref

Wolf, C

Qian, Y

Brooke, MA

Kelsell, DP

Franzke, C-W

Queen Mary Research Online