ArticleProceedings of the National Academy of Sciences of the United States of America2015
iRhoms 1 and 2 are essential upstream regulators of ADAM17-dependent EGFR signaling.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 97 papers.
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Who cites it
97 citing papers in PubMed, 158 citations in OpenAlex.
- Congenital iRHOM2 deficiency causes ADAM17 dysfunction and environmentally directed immunodysregulatory disease.Nature immunology · 2022Trial
- Review
- Comprehensive Analysis of scRNA-Seq and RNA-Seq Revealed the Role of Programmed Cell Death-Related Genes in the Prognosis of Glioblastoma Patients.Applied biochemistry and biotechnology · 2026Article
- Transferrin receptor 1 shedding by the pro-inflammatory iRhom-ADAM17 complex and ADAM10 regulates cellular iron uptake and ferroptosis.Experimental & molecular medicine · 2026Article
- Structural basis for ADAM17 activation by the iRhom1 pseudoprotease.Cell reports · 2026Article
- ADAM17 as a proteolytic rheostat linking inflammation, tissue repair, and failure of inflammatory resolution in liver injury and fibrosis.Frontiers in pharmacology · 2026Review
- Holding Out for a Model: Rhomboid Superfamily in Vertebrate Development and Disease.Journal of cellular physiology · 2025Review
- Structural insights into the activation and inhibition of the ADAM17-iRhom2 complex.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- The late-onset Alzheimer's disease risk factor RHBDF2 is a modifier of microglial TREM2 proteolysis.Life science alliance · 2025Article
- Progress of ADAM17 in Fibrosis-Related Diseases.Mediators of inflammation · 2025Review
- Low-affinity ligands of the epidermal growth factor receptor are long-range signal transmitters in collective cell migration of epithelial cells.Cell reports · 2024Article
- RHBDF1 promotes PERK expression through the JNK/FoxO3 pathway in breast cancer cells.Acta biochimica et biophysica Sinica · 2024Article
- Targeting iRhom2/ADAM17 attenuates COVID-19-induced cytokine release from cultured lung epithelial cells.Biochemistry and biophysics reports · 2024Article
- The interferon-rich skin environment regulates Langerhans cell ADAM17 to promote photosensitivity in lupus.eLife · 2024Article
- Role of iRhom2 in Olfaction: Implications for Odorant Receptor Regulation and Activity-Dependent Adaptation.International journal of molecular sciences · 2024Article
- Article
- iRhom2 regulates ectodomain shedding and surface expression of the major histocompatibility complex (MHC) class I.Cellular and molecular life sciences : CMLS · 2024Article
- Pathological mutations reveal the key role of the cytosolic iRhom2 N-terminus for phosphorylation-independent 14-3-3 interaction and ADAM17 binding, stability, and activity.Cellular and molecular life sciences : CMLS · 2024Article
- Pentapeptide PYRAE triggers ER stress-mediated apoptosis of breast cancer cells in mice by targeting RHBDF1-BiP interaction.Acta pharmacologica Sinica · 2024Article
- Inhibition of iRhom1 by CD44-targeting nanocarrier for improved cancer immunochemotherapy.Nature communications · 2024Article
37 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
11 authors at 6 institutions in 3 countries.
Funding
Abstract
The metalloproteinase ADAM17 (a disintegrin and metalloprotease 17) controls EGF receptor (EGFR) signaling by liberating EGFR ligands from their membrane anchor. Consequently, a patient lacking ADAM17 has skin and intestinal barrier defects that are likely caused by lack of EGFR signaling, and Adam17(-/-) mice die perinatally with open eyes, like Egfr(-/-) mice. A hallmark feature of ADAM17-dependent EGFR ligand shedding is that it can be rapidly and posttranslationally activated in a manner that requires its transmembrane domain but not its cytoplasmic domain. This suggests that ADAM17 is regulated by other integral membrane proteins, although much remains to be learned about the underlying mechanism. Recently, inactive Rhomboid 2 (iRhom2), which has seven transmembrane domains, emerged as a molecule that controls the maturation and function of ADAM17 in myeloid cells. However, iRhom2(-/-) mice appear normal, raising questions about how ADAM17 is regulated in other tissues. Here we report that iRhom1/2(-/-) double knockout mice resemble Adam17(-/-) and Egfr(-/-) mice in that they die perinatally with open eyes, misshapen heart valves, and growth plate defects. Mechanistically, we show lack of mature ADAM17 and strongly reduced EGFR phosphorylation in iRhom1/2(-/-) tissues. Finally, we demonstrate that iRhom1 is not essential for mouse development but regulates ADAM17 maturation in the brain, except in microglia, where ADAM17 is controlled by iRhom2. These results provide genetic, cell biological, and biochemical evidence that a principal function of iRhoms1/2 during mouse development is to regulate ADAM17-dependent EGFR signaling, suggesting that iRhoms1/2 could emerge as novel targets for treatment of ADAM17/EGFR-dependent pathologies.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.