iRhoms 1 and 2 are essential upstream regulators of ADAM17-dependent EGFR signaling.
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.
Arthritis and Tissue Degeneration Program and Departments of Biochemistry, Cell and Molecular Biology.
Xue
X
Li
Arthritis and Tissue Degeneration Program and.
Thorsten
T
Maretzky
Arthritis and Tissue Degeneration Program and.
Gisela
G
Weskamp
Tri-Institutional Laboratory of Comparative Pathology, New York, NY 10021;
Sébastien
S
Monette
Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, NY 10021;
Xiaoping
X
Qing
Arthritis and Tissue Degeneration Program and Immunology, and.
Priya Darshinee A
PD
Issuree
Department of Cancer Biology, Mayo Clinic Cancer Center, Jacksonville, FL 32224;
Howard C
HC
Crawford
Department of Gastroenterology, Hepatology, and Infectious Diseases, Heinrich Heine University, D-40225 Dusseldorf, Germany; Baxter Laboratory in Stem Cell Biology, Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305; and.
David R
DR
McIlwain
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.
Tak W
TW
Mak
Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, NY 10021;
Jane E
JE
Salmon
Arthritis and Tissue Degeneration Program and Physiology, Biophysics and Systems Biology, Weill Cornell Graduate School of Medical Sciences, New York, NY 10021; tmak@uhnresearch.ca blobelc@hss.edu.
Carl P
CP
Blobel
D051722:ADAM Proteins / Q000378:metabolism*; D000072198:ADAM17 Protein; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002469:Cell Separation; D053595:Embryonic Stem Cells / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D066246:ErbB Receptors / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D006579:Heterozygote; D019041:L-Selectin / Q000378:metabolism; D007962:Leukocytes / Q000378:metabolism; D008024:Ligands; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D002352:Carrier Proteins; D008024:Ligands; D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha; C588247:iRhom1 protein, mouse; C569468:iRhom2 protein, mouse; D019041:L-Selectin; C541485:EGFR protein, mouse; D066246:ErbB Receptors; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse
a disintegrin and metalloprotease 17; epidermal growth factor receptor; heparin-binding epidermal growth factor; inactive Rhomboid proteins; transforming growth factor alpha