ADAM17 is the Principal Ectodomain Sheddase of the EGF-Receptor Ligand Amphiregulin

Abstract

The epidermal growth factor (EGF)-receptor ligand amphiregulin (AREG) is a potent growth factor implicated in proliferative skin diseases and in primary and metastatic epithelial cancers. AREG in vitro, synthesized as a pro-peptide, requires conversion to an active peptide by metalloproteases by a process known as ectodomain shedding. Although, (Adam17) a disintegrin and metalloprotease 17 is implicated in ectodomain shedding of AREG, it remains to be established in vivo whether ADAM17 contributes to AREG shedding. In the present study, using a curly bare (Rhbdf2 cub ) mouse model that shows loss-of-hair, enlarged sebaceous glands, and rapid cutaneous wound-healing phenotypes mediated by enhanced Areg mRNA and protein levels, we sought to identify the principal ectodomain sheddase of AREG. To this end, we generated Rhbdf2 cub mice lacking ADAM17 specifically in the skin and examined the above phenotypes of Rhbdf2 cub mice. We find that ADAM17 deficiency in the skin of Rhbdf2 cub mice restores a full hair coat, prevents sebaceous-gland enlargement, and impairs the rapid wound-healing phenotype observed in Rhbdf2 cub mice. Furthermore, in vitro, stimulated shedding of AREG is abolished in Rhbdf2 cub mouse embryonic keratinocytes lacking ADAM17. Thus, our data demonstrate that ADAM17 is the major ectodomain sheddase of AREG.

Mesenchymal Stem and Stromal Cells Harness Macrophage-Derived Amphiregulin to Maintain Tissue Homeostasis

“…More intriguingly, phagocytic activity of macrophages did not influence AREG transcription, in contrast to its prominent effect on AREG secretion, which presents the possibility that MSCs induce AREG transcription and secretion through separate mechanisms and AREG secretion might share the same pathway with phagocytosis in macrophages. Because ADAM17 is the major sheddase involved in activation and release of AREG from the cell membrane (Hosur et al, 2018), we measured the expression of ADAM17 transcript and protein in macrophages, but could not find an increase in macrophage ADAM17 by MSCs. Remarkably, a series of studies have reported that AREG is secreted to a substantial part in the form of EVs and that AREG-containing EVs are highly functional in eliciting EGFR signaling in recipient cells (Higginbotham et al, 2011;Zhang et al, 2019).…”