title: iRHOM2-dependent regulation of ADAM17 in cutaneous disease and epidermal barrier function.
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.
authors.affiliation: Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Brooke
authors.affiliation: Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Etheridge
authors.affiliation: Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Nihal
authors.initials: N
authors.lastname: Kaplan
authors.affiliation: Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Simpson
authors.affiliation: Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Edel A
authors.initials: EA
authors.lastname: O'Toole
authors.affiliation: Department of Dermatology, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Akemi
authors.initials: A
authors.lastname: Ishida-Yamamoto
authors.affiliation: Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
authors.forename: Olivier
authors.initials: O
authors.lastname: Marches
authors.affiliation: Department of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Spiro
authors.initials: S
authors.lastname: Getsios
authors.affiliation: Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK d.p.kelsell@qmul.ac.uk.
authors.forename: David P
authors.initials: DP
authors.lastname: Kelsell
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000072198:ADAM17 Protein; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D003896:Desmosomes / Q000378:metabolism / Q000473:pathology; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism; D004817:Epidermis / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D015603:Keratinocytes / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D007645:Keratoderma, Palmoplantar / Q000235:genetics* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D008297:Male; D009154:Mutation; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013207:Staphylococcal Skin Infections / Q000235:genetics* / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D013211:Staphylococcus aureus / Q000502:physiology; D011503:Transglutaminases / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D016207:Cytokines; D047908:Intracellular Signaling Peptides and Proteins; C580845:RHBDF2 protein, human; D034741:RNA, Small Interfering; D004815:Epidermal Growth Factor; D011503:Transglutaminases; C512478:EGFR protein, human; D066246:ErbB Receptors; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human