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Bile acids target proteolipid nano-assemblies of EGFR and phosphatidic acid in the plasma membrane for stimulation of MAPK signaling

Bile acids are critical biological detergents in the gastrointestinal tract and also act as messengers to regulate a multitude of intracellular signaling events, including mitogenic signaling, lipid metabolism and endo/exocytosis. In particular, bile acids stimulate many receptors and ion channels o...

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Detalles Bibliográficos
Autores principales: Liang, Hong, Estes, Mary K., Zhang, Huiling, Du, Guangwei, Zhou, Yong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6118352/
https://www.ncbi.nlm.nih.gov/pubmed/30169511
http://dx.doi.org/10.1371/journal.pone.0198983
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author Liang, Hong
Estes, Mary K.
Zhang, Huiling
Du, Guangwei
Zhou, Yong
author_facet Liang, Hong
Estes, Mary K.
Zhang, Huiling
Du, Guangwei
Zhou, Yong
author_sort Liang, Hong
collection PubMed
description Bile acids are critical biological detergents in the gastrointestinal tract and also act as messengers to regulate a multitude of intracellular signaling events, including mitogenic signaling, lipid metabolism and endo/exocytosis. In particular, bile acids stimulate many receptors and ion channels on the cell surface, the mechanisms of which are still poorly understood. Membrane-associating proteins depend on the local spatial distribution of lipids in the plasma membrane (PM) for their function. Here, we report that the highly amphipathic secondary bile acid deoxycholic acid (DCA), a major constituent in the human bile, at doses <1μM enhances the nanoclustering and the PM localization of phosphatidic acid (PA) but disrupts the local segregation of phosphatidylserine in the basolateral PM of the human colorectal adenocarcinoma Caco-2 cells. PA is a key structural component of the signaling nano-domains of epidermal growth factor receptor (EGFR) on the cell surface. We show that DCA promotes the co-localization between PA and EGFR, the PA-driven EGFR dimerization/oligomerization and EGFR signaling. Depletion of PA abolishes the stimulatory effects of DCA on the EGFR oligomerization and signaling. This effect occurs in the cultured Caco-2 cells and the ex vivo human intestinal enteroids. We propose a novel mechanism, where the amphiphilic DCA monomers alter the nano-assemblies of anionic phospholipids and in turn change the dynamic structural integrity of the lipid-driven oligomerization of cell surface receptors and their signal transduction.
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spelling pubmed-61183522018-09-16 Bile acids target proteolipid nano-assemblies of EGFR and phosphatidic acid in the plasma membrane for stimulation of MAPK signaling Liang, Hong Estes, Mary K. Zhang, Huiling Du, Guangwei Zhou, Yong PLoS One Research Article Bile acids are critical biological detergents in the gastrointestinal tract and also act as messengers to regulate a multitude of intracellular signaling events, including mitogenic signaling, lipid metabolism and endo/exocytosis. In particular, bile acids stimulate many receptors and ion channels on the cell surface, the mechanisms of which are still poorly understood. Membrane-associating proteins depend on the local spatial distribution of lipids in the plasma membrane (PM) for their function. Here, we report that the highly amphipathic secondary bile acid deoxycholic acid (DCA), a major constituent in the human bile, at doses <1μM enhances the nanoclustering and the PM localization of phosphatidic acid (PA) but disrupts the local segregation of phosphatidylserine in the basolateral PM of the human colorectal adenocarcinoma Caco-2 cells. PA is a key structural component of the signaling nano-domains of epidermal growth factor receptor (EGFR) on the cell surface. We show that DCA promotes the co-localization between PA and EGFR, the PA-driven EGFR dimerization/oligomerization and EGFR signaling. Depletion of PA abolishes the stimulatory effects of DCA on the EGFR oligomerization and signaling. This effect occurs in the cultured Caco-2 cells and the ex vivo human intestinal enteroids. We propose a novel mechanism, where the amphiphilic DCA monomers alter the nano-assemblies of anionic phospholipids and in turn change the dynamic structural integrity of the lipid-driven oligomerization of cell surface receptors and their signal transduction. Public Library of Science 2018-08-31 /pmc/articles/PMC6118352/ /pubmed/30169511 http://dx.doi.org/10.1371/journal.pone.0198983 Text en © 2018 Liang et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Liang, Hong
Estes, Mary K.
Zhang, Huiling
Du, Guangwei
Zhou, Yong
Bile acids target proteolipid nano-assemblies of EGFR and phosphatidic acid in the plasma membrane for stimulation of MAPK signaling
title Bile acids target proteolipid nano-assemblies of EGFR and phosphatidic acid in the plasma membrane for stimulation of MAPK signaling
title_full Bile acids target proteolipid nano-assemblies of EGFR and phosphatidic acid in the plasma membrane for stimulation of MAPK signaling
title_fullStr Bile acids target proteolipid nano-assemblies of EGFR and phosphatidic acid in the plasma membrane for stimulation of MAPK signaling
title_full_unstemmed Bile acids target proteolipid nano-assemblies of EGFR and phosphatidic acid in the plasma membrane for stimulation of MAPK signaling
title_short Bile acids target proteolipid nano-assemblies of EGFR and phosphatidic acid in the plasma membrane for stimulation of MAPK signaling
title_sort bile acids target proteolipid nano-assemblies of egfr and phosphatidic acid in the plasma membrane for stimulation of mapk signaling
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6118352/
https://www.ncbi.nlm.nih.gov/pubmed/30169511
http://dx.doi.org/10.1371/journal.pone.0198983
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