Abstract: |
Tylosis with oesophageal cancer (TOC) is a rare familial disorder caused by cytoplasmic mutations in inactive rhomboid 2 (iRhom2 or iR2, encoded by Rhbdf2). iR2 and the related iRhom1 (or iR1, encoded by Rhbdf1) are key regulators of the membrane-anchored metalloprotease ADAM17, which is required for activating EGFR ligands and for releasing pro-inflammatory cytokines such as TNFα (or TNF). A cytoplasmic deletion in iR2, including the TOC site, leads to curly coat or bare skin (cub) in mice, whereas a knock-in TOC mutation (toc) causes less severe alopecia and wavy fur. The abnormal skin and hair phenotypes of iR2cub/cub and iR2toc/toc mice depend on amphiregulin (Areg) and Adam17, as loss of one allele of either gene rescues the fur phenotypes. Remarkably, we found that iR1-/- iR2cub/cub mice survived, despite a lack of mature ADAM17, whereas iR2cub/cub Adam17-/- mice died perinatally, suggesting that the iR2cub gain-of-function mutation requires the presence of ADAM17, but not its catalytic activity. The iR2toc mutation did not substantially reduce the levels of mature ADAM17, but instead affected its function in a substrate-selective manner. Our findings provide new insights into the role of the cytoplasmic domain of iR2 in vivo, with implications for the treatment of TOC patients. © 2023. Published by The Company of Biologists Ltd. |
Keywords: |
carrier protein; genetics; neoplasm; neoplasms; mouse; animal; metabolism; animals; mice; membrane proteins; carrier proteins; membrane protein; palmoplantar keratoderma; tumor necrosis factor alpha converting enzyme; keratoderma, palmoplantar; adam17 protein; a disintegrin and metalloprotease 17 (adam17); amphiregulin (areg); epidermal growth factor receptor ligands (egfrl); inactive rhomboid-like protein 2 (irhom2); irhom2 curly bare (cub); irhom2 tylosis with oesophageal cancer (toc); keratoderma, palmoplantar, diffuse; keratosis palmoplantaris with esophageal cancer; palmoplantar keratoderma, nonepidermolytic; irhom2 protein, mouse; rhbdf1 protein, mouse; diffuse palmoplantar keratoderma
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