Cargando…
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...
Autores principales: | , , , , |
---|---|
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 |
_version_ | 1783351914140794880 |
---|---|
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. |
format | Online Article Text |
id | pubmed-6118352 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT lianghong bileacidstargetproteolipidnanoassembliesofegfrandphosphatidicacidintheplasmamembraneforstimulationofmapksignaling AT estesmaryk bileacidstargetproteolipidnanoassembliesofegfrandphosphatidicacidintheplasmamembraneforstimulationofmapksignaling AT zhanghuiling bileacidstargetproteolipidnanoassembliesofegfrandphosphatidicacidintheplasmamembraneforstimulationofmapksignaling AT duguangwei bileacidstargetproteolipidnanoassembliesofegfrandphosphatidicacidintheplasmamembraneforstimulationofmapksignaling AT zhouyong bileacidstargetproteolipidnanoassembliesofegfrandphosphatidicacidintheplasmamembraneforstimulationofmapksignaling |