{"doi":"10.1242/jcs.260910","title":"Analysis of the function of ADAM17 in iRhom2 curly-bare and tylosis with esophageal cancer mutant mice","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.","journal":"Journal of Cell Science","year":2023,"id":360756,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":9,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.965,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":475366,"name":"Thorsten Maretzky","orcid":"0000-0003-1282-6080","position":1,"is_corresponding":false},{"id":512536,"name":"Gisela Weskamp","orcid":null,"position":2,"is_corresponding":false},{"id":511948,"name":"Coline Haxaire","orcid":"0000-0002-5463-3546","position":3,"is_corresponding":false},{"id":1113008,"name":"Johanna Tueshaus","orcid":null,"position":4,"is_corresponding":false},{"id":64859,"name":"Stefan Frieder Lichtenthaler","orcid":"0000-0003-2211-2575","position":5,"is_corresponding":false},{"id":467193,"name":"Sébastien Monette","orcid":"0000-0003-2841-6887","position":6,"is_corresponding":false},{"id":361885,"name":"Carl Blobel","orcid":"0000-0001-5053-3137","position":7,"is_corresponding":false},{"id":913557,"name":"Ariana I. Rabinowitsch","orcid":"0000-0003-0896-2119","position":0,"is_corresponding":true}],"reference_count":64,"raw_metadata":null,"created_at":"2026-07-19T01:14:06.433417Z","pmid":"37282854","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}