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Stearic acid blunts growth-factor signaling via oleoylation of GNAI proteins.

ABSTRACT: Covalent attachment of C16:0 to proteins (palmitoylation) regulates protein function. Proteins are also S-acylated by other fatty acids including C18:0. Whether protein acylation with different fatty acids has different functional outcomes is not well studied. We show here that C18:0 (stearate) and C18:1 (oleate) compete with C16:0 to S-acylate Cys3 of GNAI proteins. C18:0 becomes desaturated so that C18:0 and C18:1 both cause S-oleoylation of GNAI. Exposure of cells to C16:0 or C18:0 shifts GNAI acylation towards palmitoylation or oleoylation, respectively. Oleoylation causes GNAI proteins to shift out of cell membrane detergent-resistant fractions where they potentiate EGFR signaling. Consequently, exposure of cells to C18:0 reduces recruitment of Gab1 to EGFR and reduces AKT activation. This provides a molecular mechanism for the anti-tumor effects of C18:0, uncovers a mechanistic link how metabolites affect cell signaling, and provides evidence that the identity of the fatty acid acylating a protein can have functional consequences.

SUBMITTER: Nuskova H

PROVIDER: S-EPMC8319428 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Stearic acid blunts growth-factor signaling via oleoylation of GNAI proteins

Project description:The aim of the MS analysis is to identify fatty acids modifying Cys3 of GNAI3 in cells exposed to high C16:0 or C18:0 concentrations. Detailed description in the manuscript Nuskova et al. submitted to NatComms.

2021-08-26 | PXD027064 | Pride

Stearic acid blunts growth-factor signaling via oleoylation of GNAI proteins

Project description:The aim of the MS analysis is to identify fatty acids modifying Cys3 of GNAI3. Detailed description in the manuscript Nuskova et al. submitted to NatComms.

2021-07-22 | PXD021517 | Pride

Stearic acid alleviates aortic medial degeneration through maintaining mitochondrial dynamics homeostasis via inhibiting JNK/MAPK signaling.

Project description:Aortic dissection is characterized pathologically by aortic medial degeneration (AMD) where disturbance of mitochondrial dynamics may be involved. Stearic acid (SA) can promote mitochondrial fusion and improve mitochondrial function. Here, we established an AMD mouse model through oral administration of β-aminopropionitrile (BAPN) and a cellular model by treating primary vascular smooth muscle cells (VSMCs) with Angiotensin-II to explore the potential role of SA in AMD. Our results showed SA reduced AMD and prolonged survival of BAPN-treated mice. Excessive mitochondrial fission was observed during AMD both in vivo and in vitro, and SA reduced mitochondrial fission and increased fusion. Additionally, SA promoted expression of contractile phenotype markers of VSMCs. At the molecular level, SA reduced AMD by inhibiting JNK/MAPK signaling. Our study suggests SA can promote mitochondrial fusion and increase the contractile phenotype of VSMCs by inhibiting JNK/MAPK signaling, thereby reducing AMD formation and possibly the consequent risk of aortic dissection.

| S-EPMC11367538 | biostudies-literature

Interbacterial signaling via Burkholderia contact-dependent growth inhibition proteins

Project description:In prokaryotes and eukaryotes, cell-cell communication and recognition of self are critical to coordinate multicellular functions. While kin and kind discrimination are increasingly appreciated to shape naturally occurring microbe populations, the underlying mechanisms that govern these interbacterial interactions are insufficiently understood. Here we identify a mechanism of interbacterial signal transduction that is mediated by contact-dependent growth inhibition (CDI) system proteins. CDI systems have been characterized by their ability to deliver a polymorphic protein toxin into the cytoplasm of a neighboring bacterium, resulting in growth inhibition or death unless the recipient bacterium produces a corresponding immunity protein. Using the model organism Burkholderia thailandensis, we show that delivery of a catalytically active CDI system toxin to immune (self) bacteria results in gene expression and phenotypic changes within the recipient cells. Termed contact-dependent signaling (CDS), this response promotes biofilm formation and other community-associated behaviors. Examination of wild-type Burkholderia thailandensis and two mutant strains, each in triplicate (9 samples total). mutant BtEKA contains two amino acid substitutions (E3064A and K3066A) within the coding sequence of gene Bth_I2723. In mutant PS12-WT, the native promoter of gene Bth_I2723 has been replaced with the strong constitutive promoter of the E264 rpsL gene, PS12.

2016-08-09 | E-GEOD-83143 | biostudies-arrayexpress

Stearic Acid Induces CD11c Expression in Proinflammatory Macrophages via Epidermal Fatty Acid Binding Protein.

Project description:Obesity is associated with elevated levels of free fatty acids (FAs) and proinflammatory CD11c+ macrophages. However, whether and how free FAs contribute to CD11c+ macrophage differentiation and proinflammatory functions remain unclear. Here we report that dietary saturated FAs, but not unsaturated FAs, promoted the differentiation and function of CD11c+ macrophages. Specifically, we demonstrated that stearic acid (SA) significantly induced CD11c expression in monocytes through activation of the nuclear retinoid acid receptor. More importantly, cytosolic expression of epidermal FA binding protein (E-FABP) in monocytes/macrophages was shown to be critical to the mediation of the SA-induced effect. Depletion of E-FABP not only inhibited SA-induced CD11c upregulation in macrophages in vitro but also abrogated high-saturated-fat diet-induced skin lesions in obese mouse models in vivo. Altogether, our data demonstrate a novel mechanism by which saturated FAs promote obesity-associated inflammation through inducing E-FABP/retinoid acid receptor-mediated differentiation of CD11c+ macrophages.

| S-EPMC5940522 | biostudies-literature

Placental growth factor blunts uterine artery responses to angiotensin II.

Project description:ObjectiveChanges in maternal serum concentration of placental growth factor (PlGF) and vascular response to intravascular infusion of Angiotensin II (Ang II) follow a bell-shaped curve pattern during gestation. This study evaluates the effects of PlGF and soluble vascular endothelial growth factor receptor-1 (sFlt-1) on responses of human uterine arteries (UA) to Ang II.DesignExperimental.SettingBaylor College of Medicine and Texas Children's Hospital-Pavilion for Women.SampleUterine arteries samples (n = 14) were obtained from normotensive women undergoing caesarean hysterectomy at ?32 weeks.MethodsUterine arteries rings were incubated with (1) Krebs solution; (2) PlGF at 1.45, 14.5, and 500 pg/ml; (3) sFlt-1 at 2 ng/ml; and (4) a combination of sFlt-1, and PlGF. Dose-contraction responses to Ang II were determined in UA rings incubated in the above-mentioned conditions. Responses were also measured in presence of L-NAME or inhibitors of endothelium-derived hyperpolarising factor: apamine and charybdotoxin. The t-test was used for comparisons.Main outcome measureChanges in vascular reactivity of UA rings.ResultsPlGF blunted (P = 0.03) and sFlt-1 increased (P <0.01) the UA maximum responses to Ang II. A combination of sFlt-1 and PlGF blunted UA responses to Ang II (P < 0.05). l-NAME, apamine, and charybdotoxin reversed the relaxation effects of PlGF on UA responses to Ang II (P < 0.05).ConclusionsPlGF contributes to the blunted vascular response to Angiotensin II during normotensive pregnancies and sFlt-1 appears to attenuate this effect. PlGF and sFlt-1 may contribute to the regulation of vascular tone during pregnancy by altering the vascular response to Angiotensin II.FundingBaylor College of Medicine.Tweetable abstractPlacental growth factor and soluble vascular endothelial growth factor receptor-1 modulate the uterine artery response to Angiotensin II in normotensive pregnant women.

| S-EPMC7004274 | biostudies-literature

Fibroblast growth factor homologous factors are intracellular signaling proteins.

Project description:Fibroblast growth factors (FGFs) mediate cell growth, differentiation, migration, and morphogenesis by binding to the extracellular domain of cell surface receptors, triggering receptor tyrosine phosphorylation and signal transduction [1-5]. FGF homologous factors (FHFs) were discovered within vertebrate DNA sequence databases by virtue of their sequence similarity to FGFs [3, 6, 7], but the mechanism of FHF action has not been reported. We show here that FHF-1 is associated with the MAP kinase (MAPK) scaffold protein Islet-Brain-2 (IB2) [8] in the brain and in specific cell lines. FHF/IB2 interaction is highly specific, as FHFs do not bind to the related scaffold protein IB1(JIP-1b) [9, 10], nor can FGF-1 bind to IB2. We further show that FHFs enable IB2 to recruit a specific MAPK in transfected cells, and our data suggest that the scaffolds IB1 and IB2 have different MAPK specificities. Hence, FHFs are intracellular components of a tissue-specific protein kinase signaling module.

| S-EPMC3216481 | biostudies-literature

Autotaxin signaling via lysophosphatidic acid receptors contributes to vascular endothelial growth factor-induced endothelial cell migration.

Project description:Important roles for vascular endothelial growth factor (VEGF) and autotaxin (ATX) have been established for embryonic vasculogenesis and cancer progression. We examined whether these two angiogenic factors cooperate in regulation of endothelial cell migratory responses. VEGF stimulated expression of ATX and LPA1, a receptor for the ATX enzymatic product lysophosphatidic acid (LPA), in human umbilical vein endothelial cells. Knockdown of ATX expression significantly decreased mRNA levels for the receptors LPA1, LPA2, S1P1, S1P2, S1P3, and VEGFR2 and abolished cell migration to lysophosphatidylcholine, LPA, recombinant ATX, and VEGF. Migration to sphingosylphosphorylcholine and sphinogosine-1-phosphate was also reduced in ATX knockdown cells, whereas migration to serum remained unchanged. Furthermore, ATX knockdown decreased Akt2 mRNA levels, whereas LPA treatment strongly stimulated Akt2 expression. We propose that VEGF stimulates LPA production by inducing ATX expression. VEGF also increases LPA1 signaling, which in turn increases Akt2 expression. Akt2 is strongly associated with cancer progression, cellular migration, and promotion of epithelial-mesenchymal transition. These data show a role for ATX in maintaining expression of receptors required for VEGF and lysophospholipids to accelerate angiogenesis. Because VEGF and ATX are upregulated in many cancers, the regulatory mechanism proposed in these studies could apply to cancer-related angiogenesis and cancer progression. These data further suggest that ATX could be a prognostic factor or a target for therapeutic intervention in several cancers.

| S-EPMC2841699 | biostudies-literature

Molecular Dynamics: Investigating the Self-Association of Stearic Acid and Heteroassociation of Stearic Acid-Water in Cyclohexane.

Project description:The self-association of molecular additives determines the chemical potential in the bulk and, in turn, the adsorbed amount onto a surface for a number of important commercial applications such as wind turbines. Molecular dynamics simulations have been utilized as a technique to study the self-association of model additive, stearic acid, and heteroassociation of stearic acid-water, in cyclohexane as a function of temperature. Reasonable values of the enthalpies and equilibrium constants were determined for stearic acid in cyclohexane. The role of water, nearly always present in commercial systems, in solution association was also studied to determine the thermodynamics parameters of hydration (i.e., acid-water heteroassociation). There are very few other studies reporting on these important heteroassociation parameters. The association constants and enthalpies of association obtained from molecular dynamics are in good agreement with experimental data in the literature. A combination of Fourier transform infrared (FTIR) data and molecular dynamics simulation results allows the fraction of open dimers (single hydrogen-bonded dimers) to be estimated in cyclohexane (which is not possible from the experimental FTIR data alone). The fraction of open dimers of stearic acid in cyclohexane at room temperature is ∼1.5% at 25 °C and ∼4% at 70 °C.

| S-EPMC10633822 | biostudies-literature

Interbacterial signaling via Burkholderia contact-dependent growth inhibition proteins

2016-08-09 | GSE83143 | GEO