| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Weskamp, Gisela Issuree, Priya Darshinee A. Monette, Sébastien Li, Xue Mcilwain, David R. Mak, Tak W. Crawford, Howard C. Maretzky, Thorsten Qing, Xiaoping Blobel, Carl P. Salmon, Jane E. |
| Description |
Author Affiliation: Li X ( Arthritis and Tissue Degeneration Program and Departments of Biochemistry, Cell and Molecular Biology.); Maretzky T ( Arthritis and Tissue Degeneration Program and.); Weskamp G ( Arthritis and Tissue Degeneration Program and.); Monette S ( Tri-Institutional Laboratory of Comparative Pathology, New York, NY 10021); Qing X ( Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, NY 10021); Issuree PD ( Arthritis and Tissue Degeneration Program and Immunology, and.); Crawford HC ( Department of Cancer Biology, Mayo Clinic Cancer Center, Jacksonville, FL 32224); McIlwain DR ( Department of Gastroenterology, Hepatology, and Infectious Diseases, Heinrich Heine University, D-40225 Dusseldorf, Germany); Mak TW ( Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada M5G 2M9 tmak@uhnresearch.ca blobelc@hss.edu.); Salmon JE ( Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, NY 10021); Blobel CP ( Arthritis and Tissue Degeneration Program and Physiology, Biophysics and Systems Biology, Weill Cornell Graduate School of Medical Sciences, New York, NY 10021); |
| 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. |
| ISSN |
00278424 |
| e-ISSN |
10916490 |
| Journal |
Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number |
19 |
| Volume Number |
112 |
| Language |
English |
| Publisher |
National Academy of Sciences |
| Publisher Date |
2015-05-01 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
ADAM Proteins Metabolism Carrier Proteins Receptor, Epidermal Growth Factor Animals Cell Separation Embryonic Stem Cells Enzyme-Linked Immunosorbent Assay Fibroblasts Flow Cytometry Heterozygote L-Selectin Leukocytes Ligands Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Microglia Neoplasms Phenotype Phosphorylation Promoter Regions, Genetic Signal Transduction Tumor Necrosis Factor-alpha Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Multidisciplinary |
