A signaling cascade mediated by ceramide, src and PDGFRβ coordinates the activation of the redox-sensitive neutral sphingomyelinase-2 and sphingosine kinase-1

doi:10.1016/j.bbalip.2013.04.014

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids

Volume 1831, Issue 8, August 2013, Pages 1344-1356

https://doi.org/10.1016/j.bbalip.2013.04.014 Get rights and content

Highlights

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H2O2 sequentially activates neutral sphingomyelinase type 2 and sphingosine kinase-1.
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Low H2O2 concentration triggers S1P generation via ceramide, src and PDGFRβ.
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The nSMase2/SK1 pathway is implicated in H2O2-induced mitogenic signalling.

Abstract

Stress-inducing agents, including oxidative stress, generate the sphingolipid mediators ceramide (Cer) and sphingosine-1-phosphate (S1P) that are involved in stress-induced cellular responses. The two redox-sensitive neutral sphingomyelinase-2 (nSMase2) and sphingosine kinase-1 (SK1) participate in transducing stress signaling to ceramide and S1P, respectively; however, whether these key enzymes are coordinately regulated is not known. We investigated whether a signaling link coordinates nSMase2 and SK1 activation by H₂O₂. In mesenchymal cells, H₂O₂ elicits a dose-dependent biphasic effect, mitogenic at low concentration (5 μM), and anti-proliferative and toxic at high concentration (100 μM).

Low H₂O₂ concentration triggered activation of nSMase2 and SK1 through a nSMase2/Cer-dependent signaling pathway that acted upstream of activation of SK1. Further results implicated src and the trans-activation of PDGFRβ, as supported by the blocking effect of specific siRNAs, pharmacological inhibitors, and genetically deficient cells for nSMase2, src and SK1. The H₂O₂-induced src/PDGFRβ/SK1 signaling cascade was impaired in nSMase2-deficient fro/fro cells and was rescued by exogenous C2Cer that activated src/PDGFRβ/SK1. Thus, the results define a nSMase2/SK1 signaling pathway implicated in the mitogenic response to low oxidative stress. On the other hand, high oxidative stress induced inhibition of SK1. The results also showed that the toxicity of high H₂O₂ concentration was comparable in control and nSMase2-deficient cells. Taken together the results identify a tightly coordinated nSMase2/SK1 pathway that mediates the mitogenic effects of H₂O₂ and may sense the degree of oxidative stress.

Graphical abstract

Introduction

Sphingolipid mediators, such as ceramide (Cer), sphingosine (Sph) and sphingosine 1-phosphate (S1P), mediate cellular responses to growth factors, cytokines and stress-inducing agents [1]. The signaling function of sphingolipids has been implicated in a variety of cellular processes, including apoptosis, growth arrest, differentiation, cell survival, migration, proliferation, inflammation [2]. Some of these mediators have opposite roles, leading to the paradigm of the ‘Cer/S1P rheostat’, i.e. the balance between Cer and S1P that plays a major role in the cell fate [3]. For instance, Cer is often antimitotic and proapoptotic [2], whereas S1P is antiapoptotic and promotes cell proliferation and migration [3]. Cer plays a central role in sphingolipid metabolism, at the crossroad between de novo synthesis and degradation of more complex sphingolipids [2]. Cer can be formed by sphingomyelin (SM) breakdown by various sphingomyelinases (SMases) characterized by their optimal pH (acid, neutral or alkaline), their extracellular or subcellular localization (e.g. at the plasma membrane, in the Golgi, in lysosomes) and their mechanism of regulation [1], [2]. In the SMase family, the stress responsive neutral sphingomyelinase-2 (nSMase2) is translocated, upon stimulation, from internal subcellular compartments to the inner leaflet of the plasma membrane, where SM hydrolysis is activated by phosphatidylserine [4]. The resulting Cer can be hydrolyzed by ceramidases into Sph that can be degraded by the sphingosine lyase or re-acylated by ceramide synthase to form Cer, or phosphorylated into S1P by the two isoforms of sphingosine kinase (SK) [2]. Activated SK1 is translocated from the cytosol to cellular membranes, possibly to rafts, where it can phosphorylate Sph into S1P [5]. S1P may serve as an intracellular messenger or can be transported across the plasma membrane and act as an auto/paracrine mediator by binding to cell surface S1P receptors [3]. As activated nSMase2 and SK1 are involved in the metabolic cascade generating Cer and S1P mediators and are located in the same subcellular compartment [1], we hypothesized that these enzymes should be coordinately and finely regulated by a signaling pathway linking nSMase2 and SK1. Such a mechanism would be of major importance in cell biology since it would regulate the Cer/S1P rheostat that decides the cell fate (life or death) [1], [3].

nSMase2 is activated by ROS, H₂O₂ and GSH depletion and high oxidative stress may inhibit SK1 [6], [7], [8]. Among ROS, H₂O₂ may serve as a signaling molecule because of its diffusibility and rapid metabolism [9]. H₂O₂ triggers a variety of signaling responses, which are implicated in physiological responses [10], and in deleterious pathogenic processes [9], [11], [12], [13], in which a role for sphingolipid mediators has been reported [14], [15], [16].

As nSMase2 and SK1 are regulated by translocation from cytosol to membranes and by posttranslational modifications such as phosphorylation, ROS may act on both mechanisms to regulate these enzymes [4], [8], [17], [18]. Recent results suggest that oxidative stress-induced smooth muscle cell (SMC) proliferation is mediated by nSMase2 and SK [19], [20].

The effect of ROS on SK is apparently more puzzling, since SMC proliferation induced by ROS generated during biogenic amine oxidation or during hyperglycemic stress requires SK activity [19], [21], whereas ROS generated by biogenic amine oxidation induce SK1 inhibition and apoptosis in cardiac cells [8]. So far, it is unclear if ROS coordinately regulate nSMase-2 and SK1, or if they activate nSMase-2 and inhibit SK1, or if they both activate or inhibit the enzymes depending on the intensity of the oxidative stress.

We investigated this signaling mechanism in SMC and fibroblasts, in which exogenous H₂O₂ triggers a mitogenic response and activates nSMase2 and SK1, but also PDGFRβ that has been reported to trigger SK1 activation [22]. This led us to hypothesize that PDGFRβ could be a potential link between nSMase2 and SK1, upon activation by oxidative stress.

Our data suggest that the mitogenic effect of low H₂O₂ dose require the sequential and coordinated activation of nSMase2 and SK-1, mediated through Cer, src and PDGFRβ.

Section snippets

Chemicals

[³H]Thymidine, [choline-methyl-¹⁴C]sphingomyelin and [P³³] γ-ATP were from Perkin- Elmer (France). Anti-PDGFRβ was from Santa-Cruz, anti-phosphotyrosine protein (clone 4G10) was from Euromedex, anti-V5 was from Invitrogen and anti-pY416-src antibodies was from Cell Signaling (note that Y416-src is designated using the chicken numbering system, which is used in most of the literature (orthologous residues: in chicken Y416-src, in human Y419-src, and in mouse Y424-src, in the highly conserved

Dose-dependent mitogenic and toxic effects of H₂O₂ on SMC and fibroblasts

Exogenous H₂O₂ can enter the cell, through free diffusion and/or through diffusion facilitated by aquaporin, and can mediate downstream intracellular signaling [32]. As H₂O₂ has been shown to stimulate DNA synthesis and/or apoptosis, we first investigated the effect of variable H₂O₂ concentration in human arterial SMC (haSMC) and murine fibroblasts (mFb).

Low H₂O₂ (5 μM) triggered [³H]thymidine incorporation (DNA synthesis) and cell proliferation (increase of cell number), whereas higher H₂O₂

Discussion

H₂O₂ induces various biological effects, including mitogenic and cytotoxic responses [12]. Our data show that in cells from mesenchymatous origin, the biphasic effect of H₂O₂ is clearly dose-dependent: low concentration of H₂O₂ (5 μM) is mitogenic, whereas high concentration of H₂O₂ (100 μM) is cytotoxic. The most prominent data reported here, show that nSMase2 and SK1 are coordinately activated by low H₂O₂, leading to S1P formation and subsequent mitogenic response in SMC and fibroblasts. The

Conclusion

Finally, the major finding of the paper is the coordinated activation of nSMase2 and SK1 through a complex signaling cascade involving the interplay between lipid mediators and several kinases, which was hitherto unknown. This coordinated activation occurs through a complex signaling pathway involving nSMase2-dependent Cer, src and PDGFRβ. This allows defining an nSMase2/SK1 signaling pathway leading to the generation of S1P which is implicated in the mitogenic response of mesenchymal cells to

Sources of funding

Financial supports by INSERM, Université Toulouse-3, Agence de Biomédecine, and ANR Blanc SVSE1 “CARINA”.

Acknowledgements

The authors thank Dr. S.J. Parsons (University of Virginia, Charlottesville, VA) for Src^k + and Src^kd cells, Dr. T. Hla (Cornell University, New-York, NY) for SK1^−/− murine embryonic fibroblasts, and C. Bernis and C. Santiago for their excellent technical assistance.

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A signaling cascade mediated by ceramide, src and PDGFRβ coordinates the activation of the redox-sensitive neutral sphingomyelinase-2 and sphingosine kinase-1

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Chemicals

Dose-dependent mitogenic and toxic effects of H2O2 on SMC and fibroblasts

Discussion

Conclusion

Sources of funding

Acknowledgements

Biochim. Biophys. Acta

Arch. Biochem. Biophys.

Biochem. Biophys. Res. Commun.

J. Biol. Chem.

Prog. Lipid Res.

Trends Cell Biol.

Free Radic. Biol. Med.

J. Biol. Chem.

Free Radic. Biol. Med.

FEBS Lett.

J. Biol. Chem.

J. Immunol. Methods

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

J. Steroid Biochem. Mol. Biol.

Adv. Enzyme Regul.

Trends Biochem. Sci.

J. Biol. Chem.

Principles of bioactive lipid signalling: lessons from sphingolipids

Nat. Rev. Mol. Cell Biol.

Sphingosine-1-phosphate: an enigmatic signalling lipid

Nat. Rev. Mol. Cell Biol.

Activation of the sphingomyelin cycle by brefeldin A: effects of brefeldin A on differentiation and implications for a role for ceramide in regulation of protein trafficking

Cell Growth Differ.

Oxidative stress-dependent sphingosine kinase-1 inhibition mediates MAO-A-associated cardiac cell apoptosis

Circ. Res.

Transmitting biological information using oxygen: reactive oxygen species as signalling molecules in cardiovascular pathophysiology

Cardiovasc. Res.

J. Redox control of the survival of healthy and diseased cells

Antioxid. Redox Signal.

Dose-dependent mitogenic and toxic effects of H₂O₂ on SMC and fibroblasts