Rhomboid family member 2 regulates cytoskeletal stress-associated Keratin 16

Thiviyani Maruthappu, Anissa Chikh (), Benjamin Fell, Paul J. Delaney, Matthew A. Brooke, Clemence Levet, Angela Moncada-Pazos, Akemi Ishida-Yamamoto, Diana Blaydon, Ahmad Waseem, Irene M. Leigh, Matthew Freeman and David P. Kelsell ()
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Thiviyani Maruthappu: Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London
Anissa Chikh: Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London
Benjamin Fell: Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London
Paul J. Delaney: Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London
Matthew A. Brooke: Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London
Clemence Levet: Sir William Dunn School of Pathology
Angela Moncada-Pazos: Sir William Dunn School of Pathology
Akemi Ishida-Yamamoto: Asahikawa Medical University
Diana Blaydon: Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London
Ahmad Waseem: Centre for Clinical and Diagnostic Oral Sciences, Institute of Dentistry, Barts and the London School of Medicine and Dentistry, Queen Mary University of London
Irene M. Leigh: Centre for Centre Molecular Medicine, Clinical Research Centre, Ninewells Hospital and Medical School
Matthew Freeman: Sir William Dunn School of Pathology
David P. Kelsell: Centre for Cell Biology and Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14174

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