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Dab2 inhibits the cholesterol-dependent activation of JNK by TGF-β
Transforming growth factor-β (TGF-β) ligands activate Smad-mediated and noncanonical signaling pathways in a cell context–dependent manner. Localization of signaling receptors to distinct membrane domains is a potential source of signaling output diversity. The tumor suppressor/endocytic adaptor pro...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society for Cell Biology
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4019493/ https://www.ncbi.nlm.nih.gov/pubmed/24648493 http://dx.doi.org/10.1091/mbc.E13-09-0537 |
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author | Shapira, Keren E. Hirschhorn, Tal Barzilay, Lior Smorodinsky, Nechama I. Henis, Yoav I. Ehrlich, Marcelo |
author_facet | Shapira, Keren E. Hirschhorn, Tal Barzilay, Lior Smorodinsky, Nechama I. Henis, Yoav I. Ehrlich, Marcelo |
author_sort | Shapira, Keren E. |
collection | PubMed |
description | Transforming growth factor-β (TGF-β) ligands activate Smad-mediated and noncanonical signaling pathways in a cell context–dependent manner. Localization of signaling receptors to distinct membrane domains is a potential source of signaling output diversity. The tumor suppressor/endocytic adaptor protein disabled-2 (Dab2) was proposed as a modulator of TGF-β signaling. However, the molecular mechanism(s) involved in the regulation of TGF-β signaling by Dab2 were not known. Here we investigate these issues by combining biophysical studies of the lateral mobility and endocytosis of the type I TGF-β receptor (TβRI) with TGF-β phosphoprotein signaling assays. Our findings demonstrate that Dab2 interacts with TβRI to restrict its lateral diffusion at the plasma membrane and enhance its clathrin-mediated endocytosis. Small interfering RNA–mediated knockdown of Dab2 or Dab2 overexpression shows that Dab2 negatively regulates TGF-β–induced c-Jun N-terminal kinase (JNK) activation, whereas activation of the Smad pathway is unaffected. Moreover, activation of JNK by TGF-β in the absence of Dab2 is disrupted by cholesterol depletion. These data support a model in which Dab2 regulates the domain localization of TβRI in the membrane, balancing TGF-β signaling via the Smad and JNK pathways. |
format | Online Article Text |
id | pubmed-4019493 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | The American Society for Cell Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-40194932014-07-30 Dab2 inhibits the cholesterol-dependent activation of JNK by TGF-β Shapira, Keren E. Hirschhorn, Tal Barzilay, Lior Smorodinsky, Nechama I. Henis, Yoav I. Ehrlich, Marcelo Mol Biol Cell Articles Transforming growth factor-β (TGF-β) ligands activate Smad-mediated and noncanonical signaling pathways in a cell context–dependent manner. Localization of signaling receptors to distinct membrane domains is a potential source of signaling output diversity. The tumor suppressor/endocytic adaptor protein disabled-2 (Dab2) was proposed as a modulator of TGF-β signaling. However, the molecular mechanism(s) involved in the regulation of TGF-β signaling by Dab2 were not known. Here we investigate these issues by combining biophysical studies of the lateral mobility and endocytosis of the type I TGF-β receptor (TβRI) with TGF-β phosphoprotein signaling assays. Our findings demonstrate that Dab2 interacts with TβRI to restrict its lateral diffusion at the plasma membrane and enhance its clathrin-mediated endocytosis. Small interfering RNA–mediated knockdown of Dab2 or Dab2 overexpression shows that Dab2 negatively regulates TGF-β–induced c-Jun N-terminal kinase (JNK) activation, whereas activation of the Smad pathway is unaffected. Moreover, activation of JNK by TGF-β in the absence of Dab2 is disrupted by cholesterol depletion. These data support a model in which Dab2 regulates the domain localization of TβRI in the membrane, balancing TGF-β signaling via the Smad and JNK pathways. The American Society for Cell Biology 2014-05-15 /pmc/articles/PMC4019493/ /pubmed/24648493 http://dx.doi.org/10.1091/mbc.E13-09-0537 Text en © 2014 Shapira et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society of Cell Biology. |
spellingShingle | Articles Shapira, Keren E. Hirschhorn, Tal Barzilay, Lior Smorodinsky, Nechama I. Henis, Yoav I. Ehrlich, Marcelo Dab2 inhibits the cholesterol-dependent activation of JNK by TGF-β |
title | Dab2 inhibits the cholesterol-dependent activation of JNK by TGF-β |
title_full | Dab2 inhibits the cholesterol-dependent activation of JNK by TGF-β |
title_fullStr | Dab2 inhibits the cholesterol-dependent activation of JNK by TGF-β |
title_full_unstemmed | Dab2 inhibits the cholesterol-dependent activation of JNK by TGF-β |
title_short | Dab2 inhibits the cholesterol-dependent activation of JNK by TGF-β |
title_sort | dab2 inhibits the cholesterol-dependent activation of jnk by tgf-β |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4019493/ https://www.ncbi.nlm.nih.gov/pubmed/24648493 http://dx.doi.org/10.1091/mbc.E13-09-0537 |
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