title: Rhomboid family member 2 regulates cytoskeletal stress-associated Keratin 16.
abstract: Keratin 16 (K16) is a cytoskeletal scaffolding protein highly expressed at pressure-bearing sites of the mammalian footpad. It can be induced in hyperproliferative states such as wound healing, inflammation and cancer. Here we show that the inactive rhomboid protease RHBDF2 (iRHOM2) regulates thickening of the footpad epidermis through its interaction with K16. K16 expression is absent in the thinned footpads of irhom2-/-mice compared with irhom2+/+mice, due to reduced keratinocyte proliferation. Gain-of-function mutations in iRHOM2 underlie Tylosis with oesophageal cancer (TOC), characterized by palmoplantar thickening, upregulate K16 with robust downregulation of its type II keratin binding partner, K6. By orchestrating the remodelling and turnover of K16, and uncoupling it from K6, iRHOM2 regulates the epithelial response to physical stress. These findings contribute to our understanding of the molecular mechanisms underlying hyperproliferation of the palmoplantar epidermis in both physiological and disease states, and how this 'stress' keratin is regulated.
authors.affiliation: Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, Whitechapel London E1 2AT, UK.
authors.forename: Thiviyani
authors.initials: T
authors.lastname: Maruthappu
authors.affiliation: Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, Whitechapel London E1 2AT, UK.
authors.forename: Anissa
authors.initials: A
authors.lastname: Chikh
authors.affiliation: Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, Whitechapel London E1 2AT, UK.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Fell
authors.affiliation: Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, Whitechapel London E1 2AT, UK.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Delaney
authors.affiliation: Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, Whitechapel London E1 2AT, UK.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Brooke
authors.affiliation: Sir William Dunn School of Pathology, South Parks Road, Oxford OX1 3RE, UK.
authors.forename: Clemence
authors.initials: C
authors.lastname: Levet
authors.affiliation: Sir William Dunn School of Pathology, South Parks Road, Oxford OX1 3RE, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Moncada-Pazos
authors.affiliation: Department of Dermatology, Asahikawa Medical University, Asahikawa 078-8510, Japan.
authors.forename: Akemi
authors.initials: A
authors.lastname: Ishida-Yamamoto
authors.affiliation: Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, Whitechapel London E1 2AT, UK.
authors.forename: Diana
authors.initials: D
authors.lastname: Blaydon
authors.affiliation: Centre for Clinical and Diagnostic Oral Sciences, Institute of Dentistry, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, UK.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Waseem
authors.affiliation: Centre for Centre Molecular Medicine, Clinical Research Centre, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
authors.forename: Irene M
authors.initials: IM
authors.lastname: Leigh
authors.affiliation: Sir William Dunn School of Pathology, South Parks Road, Oxford OX1 3RE, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Freeman
authors.affiliation: Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, Whitechapel London E1 2AT, UK.
authors.forename: David P
authors.initials: DP
authors.lastname: Kelsell
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D049109:Cell Proliferation / Q000502:physiology; D003599:Cytoskeleton / Q000502:physiology; D015536:Down-Regulation; D000078404:Epidermal Cells; D004817:Epidermis / Q000502:physiology*; D004938:Esophageal Neoplasms / Q000235:genetics / Q000473:pathology; D005260:Female; D005347:Fibroblasts; D000073659:Gain of Function Mutation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D053536:Keratin-16 / Q000378:metabolism*; D053553:Keratin-6 / Q000378:metabolism; D015603:Keratinocytes / Q000502:physiology; D007645:Keratoderma, Palmoplantar / Q000235:genetics / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011312:Pressure; D034741:RNA, Small Interfering / Q000378:metabolism; D013312:Stress, Physiological / Q000502:physiology; D046509:Tissue Culture Techniques; D015854:Up-Regulation; D014945:Wound Healing / Q000502:physiology
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; C507431:KRT16 protein, human; C507569:KRT6A protein, human; D053536:Keratin-16; D053553:Keratin-6; C000629184:Krt16 protein, mouse; C580845:RHBDF2 protein, human; D034741:RNA, Small Interfering; C569468:iRhom2 protein, mouse