iRhoms 1 and 2 are essential upstream regulators of ADAM17-dependent EGFR signaling

Xue Li; Thorsten Maretzky; Gisela Weskamp; Sébastien Monette; Xiaoping Qing; Priya Darshinee A Issuree; Howard C Crawford; David R McIlwain; Tak W Mak; Jane E Salmon; Carl P Blobel

doi:10.1073/pnas.1505649112

Back

iRhoms 1 and 2 are essential upstream regulators of ADAM17-dependent EGFR signaling

Journal article

Open access

Peer reviewed

iRhoms 1 and 2 are essential upstream regulators of ADAM17-dependent EGFR signaling

Xue Li, Thorsten Maretzky, Gisela Weskamp, Sébastien Monette, Xiaoping Qing, Priya Darshinee A Issuree, Howard C Crawford, David R McIlwain, Tak W Mak, Jane E Salmon, …

Proceedings of the National Academy of Sciences - PNAS, Vol.112(19), pp.6080-6085

05/12/2015

DOI: 10.1073/pnas.1505649112

PMCID: PMC4434755

PMID: 25918388

Files and links (1)

url

https://doi.org/10.1073/pnas.1505649112View

Published (Version of record) Open Access

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.

ADAM17 Protein

Enzyme-Linked Immunosorbent Assay - methods

Neoplasms - metabolism

Tumor Necrosis Factor-alpha - metabolism

Embryonic Stem Cells - metabolism

Microglia - metabolism

Phosphorylation

Male

L-Selectin - metabolism

Receptor, Epidermal Growth Factor - metabolism

Flow Cytometry

Fibroblasts - metabolism

Promoter Regions, Genetic

Signal Transduction

Cell Separation

Mice, Inbred C57BL

Mice, Transgenic

Mice, Knockout

ADAM Proteins - metabolism

Phenotype

Animals

Carrier Proteins - metabolism

Heterozygote

Ligands

Mice

Leukocytes - metabolism

Details

Title: Subtitle: iRhoms 1 and 2 are essential upstream regulators of ADAM17-dependent EGFR signaling
Creators: Xue Li - Arthritis and Tissue Degeneration Program and Departments of Biochemistry, Cell and Molecular Biology
Thorsten Maretzky - Arthritis and Tissue Degeneration Program and
Gisela Weskamp - Arthritis and Tissue Degeneration Program and
Sébastien Monette - Tri-Institutional Laboratory of Comparative Pathology, New York, NY 10021
Xiaoping Qing - Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, NY 10021
Priya Darshinee A Issuree - Arthritis and Tissue Degeneration Program and Immunology, and
Howard C Crawford - Department of Cancer Biology, Mayo Clinic Cancer Center, Jacksonville, FL 32224
David R McIlwain - 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
Tak W Mak - 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
Jane E Salmon - Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, NY 10021
Carl P Blobel - 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
Resource Type: Journal article
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.112(19), pp.6080-6085
DOI: 10.1073/pnas.1505649112
PMID: 25918388
PMCID: PMC4434755
NLM abbreviation: Proc Natl Acad Sci U S A
ISSN: 0027-8424
eISSN: 1091-6490
Publisher: National Academy of Sciences
Grant note: 201210MFE-289576-150035 / Canadian Institutes of Health Research NIH CA008748 / Biotechnology and Biological Sciences Research Council CIHR-MOP123276 / Canadian Institutes of Health Research NIH GM64750 / NIGMS NIH HHS R01 GM064750 / NIGMS NIH HHS NIH CA159222 / NCI NIH HHS P30 CA008748 / NCI NIH HHS R01 CA159222 / NCI NIH HHS
Language: English
Date published: 05/12/2015
Academic Unit: Infectious Diseases; Internal Medicine
Record Identifier: 9984094575102771

Metrics

19 Record Views

118 Times Cited - Web of Science

See more details