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- Publisher Website: 10.1073/pnas.1505649112
- Scopus: eid_2-s2.0-84929224114
- PMID: 25918388
- WOS: WOS:000354390600066
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Article: iRhoms 1 and 2 are essential upstream regulators of ADAM17-dependent EGFR signaling
Title | iRhoms 1 and 2 are essential upstream regulators of ADAM17-dependent EGFR signaling |
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Authors | |
Keywords | Transforming growth factor alpha Inactive rhomboid proteins A disintegrin and metalloprotease 17 Epidermal growth factor receptor Heparin-binding epidermal growth factor |
Issue Date | 2015 |
Citation | Proceedings of the National Academy of Sciences of the United States of America, 2015, v. 112, n. 19, p. 6080-6085 How to Cite? |
Abstract | © 2015, National Academy of Sciences. All rights reserved. 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. |
Persistent Identifier | http://hdl.handle.net/10722/292883 |
ISSN | 2023 Impact Factor: 9.4 2023 SCImago Journal Rankings: 3.737 |
PubMed Central ID | |
ISI Accession Number ID |
DC Field | Value | Language |
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dc.contributor.author | Li, Xue | - |
dc.contributor.author | Maretzky, Thorsten | - |
dc.contributor.author | Weskamp, Gisela | - |
dc.contributor.author | Monette, Sébastien | - |
dc.contributor.author | Qing, Xiaoping | - |
dc.contributor.author | Issuree, Priya Darshinee A. | - |
dc.contributor.author | Crawford, Howard C. | - |
dc.contributor.author | McIlwain, David R. | - |
dc.contributor.author | Mak, Tak W. | - |
dc.contributor.author | Salmon, Jane E. | - |
dc.contributor.author | Blobel, Carl P. | - |
dc.date.accessioned | 2020-11-17T14:57:25Z | - |
dc.date.available | 2020-11-17T14:57:25Z | - |
dc.date.issued | 2015 | - |
dc.identifier.citation | Proceedings of the National Academy of Sciences of the United States of America, 2015, v. 112, n. 19, p. 6080-6085 | - |
dc.identifier.issn | 0027-8424 | - |
dc.identifier.uri | http://hdl.handle.net/10722/292883 | - |
dc.description.abstract | © 2015, National Academy of Sciences. All rights reserved. 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<sup>-/-</sup> mice die perinatally with open eyes, like Egfr<sup>-/-</sup> 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<sup>-/-</sup> mice appear normal, raising questions about how ADAM17 is regulated in other tissues. Here we report that iRhom1/2<sup>-/-</sup> double knockout mice resemble Adam17<sup>-/-</sup> and Egfr<sup>-/-</sup> 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<sup>-/-</sup> 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. | - |
dc.language | eng | - |
dc.relation.ispartof | Proceedings of the National Academy of Sciences of the United States of America | - |
dc.subject | Transforming growth factor alpha | - |
dc.subject | Inactive rhomboid proteins | - |
dc.subject | A disintegrin and metalloprotease 17 | - |
dc.subject | Epidermal growth factor receptor | - |
dc.subject | Heparin-binding epidermal growth factor | - |
dc.title | iRhoms 1 and 2 are essential upstream regulators of ADAM17-dependent EGFR signaling | - |
dc.type | Article | - |
dc.description.nature | link_to_OA_fulltext | - |
dc.identifier.doi | 10.1073/pnas.1505649112 | - |
dc.identifier.pmid | 25918388 | - |
dc.identifier.pmcid | PMC4434755 | - |
dc.identifier.scopus | eid_2-s2.0-84929224114 | - |
dc.identifier.volume | 112 | - |
dc.identifier.issue | 19 | - |
dc.identifier.spage | 6080 | - |
dc.identifier.epage | 6085 | - |
dc.identifier.eissn | 1091-6490 | - |
dc.identifier.isi | WOS:000354390600066 | - |
dc.identifier.issnl | 0027-8424 | - |