A retinoic acid receptor RARα pool present in membrane lipid rafts forms complexes with G protein αQ to activate p38MAPK

Piskunov, Aleksandr; Rochette‐Egly, Cécile

doi:10.1038/onc.2011.499

Cited by 89 publications

(91 citation statements)

References 52 publications

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“…Furthermore, our work does not preclude synergistic/parallel effects on other signalling pathways. For example, the positive effect of omega-3 PUFA supplementation on neurogenesis in aging occur in parallel with restorative effects on the retinoic acid receptors, RARalpha and RXRbeta in CA1 and dentate gyrus regions of the hippocampus, suggesting some of the effects may be mediated by activity at these transcription factors (Dyall et al, 2010), or interaction between p38 MAPK and retinoid signalling (Piskunov and Rochette-Egly, 2012).…”

mentioning

confidence: 99%

Distinctive effects of eicosapentaenoic and docosahexaenoic acids in regulating neural stem cell fate are mediated via endocannabinoid signalling pathways

et al. 2016

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Running title: EPA, but not DHA induces proliferation in NSCs Abbreviations: AA, Arachidonic acid, AEA, anandamide, DHA. Docosahexaenoic acid; EPA, eicosapentaenoic acid, 2-AG, 2-arachidonylglycerol 2 Title: Distinctive effects of eicosapentaenoic and docosahexaenoic acids in regulating neural stem cell fate are mediated via endocannabinoid signalling pathways Emerging evidence suggests a complex interplay between the endocannabinoid system, omega-3 fatty acids and the immune system in the promotion of brain self-repair. However, it is unknown if all omega-3 fatty acids elicit similar effects on adult neurogenesis and if such effects are mediated or regulated by interactions with the endocannabinoid system. This study investigated the effects of DHA and EPA on neural stem cell (NSC) fate and the role of the endocannabinoid signalling pathways in these effects.EPA, but not DHA, significantly increased proliferation of NSCs compared to controls, an effect associated with enhanced levels of the endocannabinoid 2-arachidonylglycerol (2-AG) and p-p38 MAPK, effects attenuated by pre-treatment with CB1 (AM251) or CB2 (AM630) receptor antagonists. Furthermore, in NSCs derived from IL-1 deficient mice, EPA significantly decreased proliferation and p-p38 MAPK levels compared to controls, suggesting a key role for IL-1 signalling in the effects observed. Although DHA similarly increased 2-AG levels in wild-type NSCs, there was no concomitant increase in proliferation or p-p38 MAPK activity. In addition, in NSCs from IL-1 deficient mice, DHA significantly increased proliferation without effects on p-P38 MAPK, suggesting effects of DHA are mediated via alternative signalling pathways. These results provide crucial new insights into the divergent effects of EPA and DHA in regulating NSC proliferation and the pathways involved, and highlight the therapeutic potential of their interplay with endocannabinoid signalling in brain repair.

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confidence: 99%

Distinctive effects of eicosapentaenoic and docosahexaenoic acids in regulating neural stem cell fate are mediated via endocannabinoid signalling pathways

et al. 2016

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“…7A) (18) and the nongenomic effects of RA, i.e., the activation of the p38MAPK pathway, were abrogated ( Fig. 7B) (14). Consequently, SRC-3 was not phosphorylated at S860 (Fig.…”

Section: Src-3 Is Not Phosphorylated Nor Degraded In Erbb-2 Positive mentioning

confidence: 97%

“…2B). According to our previous studies (6,13), p38MAPK is rapidly activated in response to RA through nongenomic effects (14) and phosphorylates SRC-3 (6) and several other targets. SRC-3 depicts 4 p38MAPK consensus phosphorylation sites: S505, S543, S860, and S867 ( Fig.…”

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confidence: 99%

“…Next, to explore further the interaction between CUL-3 and SRC-3 phosphorylated at S860, we used a proximity ligation assay (PLA) (14,15), which allows the in situ detection of interacting endogenous proteins. Rabbit anti-CUL-3 and mouse anti-phospho-SRC-3 antibodies were used followed by speciesspecific secondary antibodies, called PLA probes, each attached with a unique short DNA strand.…”

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confidence: 99%

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Cullin 3 mediates SRC-3 ubiquitination and degradation to control the retinoic acid response

Ferry¹,

Gaouar²,

Fischer

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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SRC-3 is an important coactivator of nuclear receptors including the retinoic acid (RA) receptor α. Most of SRC-3 functions are facilitated by changes in the posttranslational code of the protein that involves mainly phosphorylation and ubiquitination. We recently reported that SRC-3 is degraded by the proteasome in response to RA. Here, by using an RNAi E3-ubiquitin ligase entry screen, we identified CUL-3 and RBX1 as components of the E3 ubiquitin ligase involved in the RA-induced ubiquitination and subsequent degradation of SRC-3. We also show that the RA-induced ubiquitination of SRC-3 depends on its prior phosphorylation at serine 860 that promotes binding of the CUL-3–based E3 ligase in the nucleus. Finally, phosphorylation, ubiquitination, and degradation of SRC-3 cooperate to control the dynamics of transcription. In all, this process participates to the antiproliferative effect of RA.

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“…In addition, MAPK can be activated or inactivated by atRA through a mechanism that is independent of RAR-/ RXR-mediated gene transcription [34,35]. This nongenomic mechanism of atRA action involves RAR pools present in the cytosol or at the plasma membrane, and the incorporation of these RAR into signaling complexes that modulate MAPK activity [36]. Activated MAPK phosphorylate various targets, including RAR and RXR, themselves and their coregulators, and thus fine tune positively or negatively the transcriptional activity of these receptors.…”

Section: Stem Cells and Developmentmentioning

confidence: 99%

Differential Effects of Retinoids and Inhibitors of ERK and p38 Signaling on Adipogenic and Myogenic Differentiation of P19 Stem Cells

Bouchard

Paquin

2013

Stem Cells and Development

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All-trans-retinoic acid (atRA) is an essential signaling molecule in embryonic development. It regulates cell differentiation by activating nuclear retinoic acid receptors (RAR) and retinoid-X receptors (RXR), which both control gene expression. In addition, atRA could act in the cytoplasm by modulating the activity of mitogenactivated protein kinases (MAPK) ERK and p38, which also have a role in cell differentiation. AtRA can induce the differentiation of P19 embryonic carcinoma stem cells into adipocytes, cardiomyocytes, and skeletal muscle cells, concurrently, in the same culture. We postulated that combinations of atRA, atRA analogs exhibiting selectivity for RAR or RXR, and inhibitors of ERK and p38 signaling (ERKi and p38i) could be used to favor one mesodermal fate over the others in the P19 model. In a first series of experiments, we replaced atRA by an agonist of RXR (LG100268) or RAR (TTNPB) to preferentially stimulate one group of receptors over the other.LG100268 was as adipogenic and myogenic as atRA, whereas TTNPB strongly induced adipogenesis, but not myogenesis. ERKi enhanced the myogenic action of atRA, and p38i increased both adipogenesis and myogenesis. In a second series of experiments, we combined atRA with an RAR or RXR antagonist (RARatg or RXRatg) to preferentially deactivate each receptor group in turn. The combinations atRA + RXRatg and atRA + RARatg, including or not ERKi, had similar mesodermal actions as atRA. In contrast, there was no myogenesis with atRA + RXRatg + p38i treatment, and there were no myogenesis and no adipogenesis with the atRA + RARatg + p38i combination. Overall, the results indicate that p38 has a role in mesodermal differentiation that depends on the retinoid context. Indeed, p38 in conjunction with RXR is important in myogenesis, and p38 and RAR in adipogenesis. Under the conditions tested, it was possible to stimulate adipogenesis with a block on myogenesis, whereas increased myogenesis was accompanied by adipogenesis.

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A retinoic acid receptor RARα pool present in membrane lipid rafts forms complexes with G protein αQ to activate p38MAPK

Cited by 89 publications

References 52 publications

Distinctive effects of eicosapentaenoic and docosahexaenoic acids in regulating neural stem cell fate are mediated via endocannabinoid signalling pathways

Distinctive effects of eicosapentaenoic and docosahexaenoic acids in regulating neural stem cell fate are mediated via endocannabinoid signalling pathways

Cullin 3 mediates SRC-3 ubiquitination and degradation to control the retinoic acid response

Differential Effects of Retinoids and Inhibitors of ERK and p38 Signaling on Adipogenic and Myogenic Differentiation of P19 Stem Cells

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