iRHOM2-dependent regulation of ADAM17 in cutaneous disease and epidermal barrier function.
Hum Mol Genet
; 23(15): 4064-76, 2014 Aug 01.
Article
em En
| MEDLINE
| ID: mdl-24643277
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Infecções Cutâneas Estafilocócicas
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Neoplasias Esofágicas
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Proteínas de Transporte
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Queratinócitos
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Ceratodermia Palmar e Plantar
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Epiderme
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Proteínas ADAM
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article