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Hum Mol Genet. 2014 Aug 1;23(15):4064-76. doi: 10.1093/hmg/ddu120. Epub 2014 Mar 18.

iRHOM2-dependent regulation of ADAM17 in cutaneous disease and epidermal barrier function.

Author information

1
Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
2
Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
3
Department of Dermatology, Asahikawa Medical University, Asahikawa, Japan.
4
Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK d.p.kelsell@qmul.ac.uk.

Abstract

iRHOM2 is a highly conserved, catalytically inactive member of the Rhomboid family, which has recently been shown to regulate the maturation of the multi-substrate ectodomain sheddase enzyme ADAM17 (TACE) in macrophages. Dominant iRHOM2 mutations are the cause of the inherited cutaneous and oesophageal cancer-susceptibility syndrome tylosis with oesophageal cancer (TOC), suggesting a role for this protein in epithelial cells. Here, using tissues derived from TOC patients, we demonstrate that TOC-associated mutations in iRHOM2 cause an increase in the maturation and activity of ADAM17 in epidermal keratinocytes, resulting in significantly upregulated shedding of ADAM17 substrates, including EGF-family growth factors and pro-inflammatory cytokines. This activity is accompanied by increased EGFR activity, increased desmosome processing and the presence of immature epidermal desmosomes, upregulated epidermal transglutaminase activity and heightened resistance to Staphylococcal infection in TOC keratinocytes. Many of these features are consistent with the presence of a constitutive wound-healing-like phenotype in TOC epidermis, which may shed light on a novel pathway in skin repair, regeneration and inflammation.

PMID:
24643277
PMCID:
PMC4110483
DOI:
10.1093/hmg/ddu120
[Indexed for MEDLINE]
Free PMC Article

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