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

Date Published: August 31, 2018

Publisher: Public Library of Science

Author(s): Hong Liang, Mary K. Estes, Huiling Zhang, Guangwei Du, Yong Zhou, Sheereen Majd.

http://doi.org/10.1371/journal.pone.0198983

Abstract

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.

Partial Text

Bile acids are synthesized in the liver, stored in the gallbladder and secreted into the small intestine as a component of the enterohepatic circulation [1]. As biological detergents, the bile acids above their critical micelle concentrations (CMCs) form micelles to emulsify fat-soluble molecules to facilitate digestion of fatty acids and lipids in food. The bile acid micelles also act as vehicles to incorporate endogenous and exogenous hydrophobic waste for excretion. Bile acid concentrations vary widely in human body. Specifically, the secondary bile acid, deoxycholic acid (DCA), is a major organic component of human bile, comprising 25–35% of all bile content [2]. While the CMC of DCA is 5-7mM in physiological buffer [3], DCA concentration is < 2μM in the plasma and in the range of 250–350μM in the colon [2]. At the doses well below their CMCs, the bile acids impact cell signaling cascades, including lipid metabolism, mitogenic signaling, ion channel activation, as well as protein trafficking [4]. These signaling effects contribute to the bile acid-induced pathophysiological conditions, including cholestasis, inflammatory bowel disease and cancer in the GI tract [5, 6]. The ability of bile acids to stimulate the nuclear receptors partially contributes to the bile acid-induced changes in cell function and has been studied extensively [7]. However, how the bile acids activate a variety of cell surface receptors is still poorly understood. Our current study aims to explore potential molecular mechanism(s) for the bile acid-induced activation of the cell surface EGF receptor. We found that the secondary bile acid DCA has selective effects on the spatial distribution of different acidic lipids in the PM of the Caco-2 cells. Especially, DCA markedly enhances the local spatial aggregation of PA, which in turn induces the co-localization between PA and EGFR, promotes the EGFR dimerization/oligomerization and stimulates the EGFR-MAPK signaling. Acute PA depletion effectively abolishes the DCA-induced EGFR oligomerization and the DCA stimulation of the EGFR-MAPK signaling. This effect has been observed in both the cultured human colon cancer cell line and the ex vivo human intestinal enteroids. Thus, the dynamic nano-domains of the anionic lipids in the PM may act as the signaling platforms to mediate the bile acid stimulation of the cell surface receptors. Here we propose that the secondary bile acid, DCA, stimulates EGFR-MAPK signaling via modulating the dynamic spatial distribution of minor acidic lipids in the PM. DCA has distinct effects on different PM lipids, which potentially leads to highly diverse responses from various lipid-dependent surface receptors, ion channels and other membrane-associating proteins. This lipid-mediated effect potentially contributes to the diverse biological and pathophysiological effects of bile acids.   Source: http://doi.org/10.1371/journal.pone.0198983

 

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