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 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.
Highlights
Keratinocytes mainly supports proliferation and survival but prevents differentiation
We demonstrate that ADAM17-dependent EGFR signalling directly induces transglutaminase 1 (TG1) expression in keratinocytes committed to terminal differentiation prominently through phospholipase C γ1 (PLCγ1 ) and protein kinase C (PKC) pathways
We previously demonstrated that lack of Adam[17] in differentiated murine keratinocytes leads to significantly reduced TG activity and decreased expression of TG1 and TG313 as well as reduced Tgm[5] transcription
Summary
Keratinocytes mainly supports proliferation and survival but prevents differentiation. ADAM17 (a disintegrin and metalloproteinase 17) or tumor necrosis factor α-converting enzyme (TACE) is a membrane-anchored metalloproteinase that was originally identified to cleave membrane-bound tumor necrosis factor (TNF)-αby a process named as ectodomain shedding[19] This protease is known as crucial upstream regulator of EGFR signalling by shedding of the majority of EGFR ligands[20]. Our investigations on AD17ΔKC and EgfrΔKC mice revealed that ADAM17/EGFR axis sustained the CE formation and postnatal skin barrier stability by tightly regulation of the expression and proteolytic processing of several CE components, especially by supporting TG activity[13,26]. Topical skin application of cholesterol sulfate, an activator of PKCη,significantly improved TG activity in epidermis of AD17ΔKC mice These findings will help to uncover novel therapeutic strategies for inflammatory skin diseases related to disrupted EGFR signalling
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
