The xenoestrogens biphenol‐A and nonylphenol differentially regulate metalloprotease‐mediated shedding of EGFR ligands

Paulina Urriola‐Muñoz; Xue Li; Thorsten Maretzky; David R. McIlwain; Tak W. Mak; Juan G. Reyes; Carl P. Blobel; Ricardo D. Moreno

doi:10.1002/jcp.26097

journal article Aug 25, 2017

The xenoestrogens biphenol‐A and nonylphenol differentially regulate metalloprotease‐mediated shedding of EGFR ligands

Paulina Urriola‐Muñoz Xue Li

Thorsten Maretzky David R. McIlwain

Tak W. Mak

Juan G. Reyes Carl P. Blobel Ricardo D. Moreno

Journal of Cellular Physiology Vol. 233 No. 3 pp. 2247-2256 · Wiley

View at Publisher Save 10.1002/jcp.26097

Abstract

The xenoestrogens bisphenol‐A (BPA) and nonylphenol (NP) are endocrine disruptors used in the plastic polymer industry to manufacture different products for human use. Previous studies have suggested a role of these compounds in the shedding of signaling molecules, such as tumor necrosis factor α (TNF‐α). The aim of this work was to evaluate the effect of BPA and NP on the sheddase ADAM17 and its newly discovered regulators iRhom1 and iRhom2 in the release of EGFR‐ligands. We report that BPA and NP can stimulate the release of the ADAM17‐substrates HB‐EGF and TGF‐α. In cells lacking ADAM17 (Adam17−/− mEFs) BPA‐stimulated release of HB‐EGF, but not TGF‐α, was strongly reduced, whereas NP‐stimulated shedding of HB‐EGF and TGF‐α was completely abolished. Inactivation of both ADAM17 and the related ADAM10 (Adam10/17−/− mEFs) completely prevented the release of these substrates. In the absence of iRhom1, BPA‐ or NP‐stimulated release of HB‐EGF or TGF‐α was comparable to wild‐type control mEFs, conversely the BPA‐induced release of HB‐EGF was abolished in iRhom2−/− mEFs. The defect in shedding of HB‐EGF in iRhom2−/− mEF cells could be rescued by overexpressing iRhom2. Interestingly, the NP‐stimulated release of HB‐EGF was not affected by the absence of iRhom2, suggesting that NP could potentially activate both ADAM10 and ADAM17. We tested this hypothesis using betacellulin (BTC), an EGFR‐ligand that is a substrate for ADAM10. We found that NP, but not BPA stimulated the release of BTC in Adam17−/−, iRhom2−/−, or iRhom1/2−/−, but not in Adam10/17−/− cells. Taken together, our results suggest that BPA and NP stimulate the release of EGFR‐ligands by differentially activating ADAM17 or ADAM10. The identification of specific effects of these endocrine disruptors on ADAM10 and ADAM17 will help to provide a better understanding of their roles in cell signaling and proinflammatory processes, and provide new potential targets for treatment of reproductive or inflammatory diseases such as asthma or breast cancer that are promoted by xenoestrogens.

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Details

Published: Aug 25, 2017
Vol/Issue: 233(3)
Pages: 2247-2256
License: View

Authors

P

Paulina Urriola‐Muñoz

Facultad de Ciencias Biológicas, Departamento de Fisiología Pontificia Universidad Católica de Chile Santiago Chile; Instituto de Química Pontificia Universidad Católica de Valparaíso Valparaíso Chile

X

Xue Li

Arthritis and Tissue Degeneration Program Hospital for Special Surgery New York New York; Department of Biochemistry, Cellular and Molecular Biology Weill Cornell Graduate School of Medical Sciences New York New York

T

Thorsten Maretzky

Arthritis and Tissue Degeneration Program Hospital for Special Surgery New York New York

D

David R. McIlwain

Department of Microbiology and Immunology, Baxter Laboratory in Stem Cell Biology Stanford University Stanford California

T

Tak W. Mak

Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Center University Health Network Toronto, Ontario Canada

J

Juan G. Reyes

Instituto de Química Pontificia Universidad Católica de Valparaíso Valparaíso Chile

C

Carl P. Blobel

Arthritis and Tissue Degeneration Program Hospital for Special Surgery New York New York; Institute for Advanced Study Technische Universität München Garching Germany; Department of Physiology, Biophysics and Systems Biology Weill Cornell University New York New York

R

Ricardo D. Moreno

Facultad de Ciencias Biológicas, Departamento de Fisiología Pontificia Universidad Católica de Chile Santiago Chile

Funding

NIH Office of the Director Award: GM64750

Fondo Nacional de Desarrollo Cientìfico y Tecnológico Award: 1110778

Cite This Article

Paulina Urriola‐Muñoz, Xue Li, Thorsten Maretzky, et al. (2017). The xenoestrogens biphenol‐A and nonylphenol differentially regulate metalloprotease‐mediated shedding of EGFR ligands. Journal of Cellular Physiology, 233(3), 2247-2256. https://doi.org/10.1002/jcp.26097

The xenoestrogens biphenol‐A and nonylphenol differentially regulate metalloprotease‐mediated shedding of EGFR ligands

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