Enzyme Responsible for Skin Thickening Disorder Linked to Esophageal Cancer

K16 is a cytoskeletal scaffolding protein highly expressed at pressure-bearing sites of the mammalian footpad, which can be induced in hyperproliferative states such as wound healing, inflammation, and cancer.

The investigators found that mice that had been genetically engineered to lack the iRHOM2 gene had abnormally thin paw skin, while humans with mutations that increased the expression of iRHOM2 had thickened palms and soles with callouses, and that a high percentage of these patients developed esophageal cancer.

At the molecular level, the investigators found that iRHOM2 bound to K16, and that this interaction was increased in TOC keratinocytes, where it was associated with robust downregulation of K16’s binding partner K6. In humans and mice, iRHOM2 loss resulted in dampened proliferation and reduced K16 expression, and in mice this led to thinning of epidermis in the footpad.

The authors concluded that, "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. These findings highlight a novel and fundamental role for iRHOM2 in regulating the epithelial response to mechanical stress."