Analysis of the function of ADAM17 in iRhom2 curly-bare and tylosis with esophageal cancer mutant mice

Ariana I. Rabinowitsch, Thorsten Maretzky, Gisela Weskamp, Coline Haxaire, Johanna Tueshaus, Stefan F. Lichtenthaler, Sébastien Monette, Carl P. Blobel

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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.

Original languageEnglish
Article numberjcs260910
JournalJournal of Cell Science
Issue number13
StatePublished - Jul 2023


  • 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)


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