Rhomboid family member 2 regulates cytoskeletal stress-associated Keratin 16

Citations Over TimeTop 10% of 2017 papers

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.

Related Papers

• → Keratin expression in human tissues and neoplasms(2002)827 cited
• → Keratin intermediate filaments in the colon: guardians of epithelial homeostasis(2020)57 cited
• → Lessons from Keratin 18 Knockout Mice: Formation of Novel Keratin Filaments, Secondary Loss of Keratin 7 and Accumulation of Liver-specific Keratin 8-Positive Aggregates(1998)207 cited
• → Keratin 19 in the adult human prostate: tissue and cell culture studies(1996)28 cited
• → Out of balance: consequences of a partial keratin 10 knockout(1997)44 cited