Analysis of the function of ADAM17 in iRhom2 curly-bare and tylosis with esophageal cancer mutant mice
| Autor: | Rabinowitsch, Ariana I, Maretzky, Thorsten, Weskamp, Gisela, Haxaire, Coline, Tueshaus, Johanna, Lichtenthaler, Stefan F, Monette, Sébastien, Blobel, Carl P |
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| Jazyk: | angličtina |
| Rok vydání: | 2023 |
| Předmět: |
Keratoderma
Palmoplantar Diffuse Amphiregulin (AREG) iRhom2 Curly bare (Cub) genetics [ADAM17 Protein] genetics [Keratoderma Palmoplantar] Membrane Proteins Inactive rhomboid-like protein 2 (iRhom2) ADAM17 Protein genetics [Carrier Proteins] iRhom2 tylosis with oesophageal cancer (TOC) Mice metabolism [ADAM17 Protein] genetics [Membrane Proteins] A disintegrin and metalloprotease 17 (ADAM17) ddc:570 Neoplasms Rhbdf1 protein mouse iRhom2 protein mouse Animals Carrier Proteins Epidermal growth factor receptor ligands (EGFRL) |
| Zdroj: | Journal of cell science 136(13), jcs260910 (2023). doi:10.1242/jcs.260910 |
| DOI: | 10.1242/jcs.260910 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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