Journal article
Analysis of the function of ADAM17 in iRhom2-curly-bare (cub) and Tylosis with Oesophageal Cancer (TOC) mutant mice
Journal of cell science, Vol.136(13), jcs260910
07/2023
DOI: 10.1242/jcs.260910
PMCID: PMC10357010
PMID: 37282854
Abstract
Tylosis with Oesophageal Cancer (TOC), is a rare familial disorder caused by cytoplasmic mutations in inactive rhomboid 2 (iR2). iR2 and the related iR1 are key regulators of the membrane-anchored metalloprotease ADAM17, which is required for activating EGFR ligands and for releasing pro-inflammatory cytokines such as TNFa. A cytoplasmic deletion in iR2, including the TOC site, leads to curly whiskers and bare skin (cub) in mice, whereas a knock-in TOC mutation causes less severe alopecia and wavy fur. The abnormal skin and hair phenotypes of iR2cub/cub and iR2toc/toc mice depend on amphiregulin and ADAM17, since loss of one allele of either gene rescues the fur phenotypes. Remarkably, iR1-/-iR2cub/cub mice survive, despite a lack of mature ADAM17, whereas iR2cub/cubAdam17-/-mice die perinatally, suggesting that the iR2cub gain-of-function mutation requires the presence of ADAM17, but not its catalytic activity. iR2toc does not substantially reduce the levels of mature ADAM17, but instead affects 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.
Details
- Title: Subtitle
- Analysis of the function of ADAM17 in iRhom2-curly-bare (cub) and Tylosis with Oesophageal Cancer (TOC) mutant mice
- Creators
- Ariana I Rabinowitsch - Tri-Institutional PhD Program in Chemical BiologyThorsten Maretzky - University of IowaGisela Weskamp - Hospital for Special SurgeryColine Haxaire - Hospital for Special SurgeryJohanna Tueshaus - Institute for Advanced StudyStefan F Lichtenthaler - German Center for Neurodegenerative DiseasesSébastien Monette - Rockefeller UniversityCarl P Blobel - Tri-Institutional PhD Program in Chemical Biology
- Resource Type
- Journal article
- Publication Details
- Journal of cell science, Vol.136(13), jcs260910
- DOI
- 10.1242/jcs.260910
- PMID
- 37282854
- PMCID
- PMC10357010
- NLM abbreviation
- J Cell Sci
- ISSN
- 0021-9533
- eISSN
- 1477-9137
- Grant note
- DOI: 10.13039/100000002, name: National Institutes of Health, award: T32GM007739; DOI: 10.13039/100000057, name: National Institute of General Medical Sciences, award: R35 GM134907; DOI: 10.13039/100000057, name: National Institute of General Medical Sciences; name: National Cancer Institute, award: P30 CA008748; DOI: 10.13039/501100001659, name: Deutsche Forschungsgemeinschaft, award: EXC 2145 SyNergy ID 390857198
- Language
- English
- Electronic publication date
- 06/07/2023
- Date published
- 07/2023
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984426853702771
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