Dey N, De PK, Wang M, Zhang H, Dobrota EA, Robertson KA et al.. CSK controls retinoic acid receptor (RAR) signaling: a RAR-c-SRC signaling axis is required for neuritogenic differentiation. Mol Cell Biol 27: 4179-4197

Section of Pediatric Hematology/Oncology, Department of Pediatrics, Aflac Cancer Center and Blood Disorders Services, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA 30022, USA.
Molecular and Cellular Biology (Impact Factor: 5.04). 07/2007; 27(11):4179-97. DOI: 10.1128/MCB.01352-06
Source: PubMed

ABSTRACT Herein, we report the first evidence that c-SRC is required for retinoic acid (RA) receptor (RAR) signaling, an observation that suggests a new paradigm for this family of nuclear hormone receptors. We observed that CSK negatively regulates RAR functions required for neuritogenic differentiation. CSK overexpression inhibited RA-mediated neurite outgrowth, a result which correlated with the inhibition of the SFK c-SRC. Consistent with an extranuclear effect of CSK on RAR signaling and neurite outgrowth, CSK overexpression blocked the downstream activation of RAC1. The conversion of GDP-RAC1 to GTP-RAC1 parallels the activation of c-SRC as early as 15 min following all-trans-retinoic acid treatment in LA-N-5 cells. The cytoplasmic colocalization of c-SRC and RARgamma was confirmed by immunofluorescence staining and confocal microscopy. A direct and ligand-dependent binding of RAR with SRC was observed by surface plasmon resonance, and coimmunoprecipitation studies confirmed the in vivo binding of RARgamma to c-SRC. Deletion of a proline-rich domain within RARgamma abrogated this interaction in vivo. CSK blocked the RAR-RA-dependent activation of SRC and neurite outgrowth in LA-N-5 cells. The results suggest that transcriptional signaling events mediated by RA-RAR are necessary but not sufficient to mediate complex differentiation in neuronal cells. We have elucidated a nongenomic extranuclear signal mediated by the RAR-SRC interaction that is negatively regulated by CSK and is required for RA-induced neuronal differentiation.

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Available from: Donald L Durden, Aug 26, 2015
    • "Moreover, gene regulation in the brain subserves specific functions different from those of other cells. Finally, we observed RARb in the cytoplasm as described in breast and neuroblastoma cells (Sommer et al. 1999; Dey et al. 2007; Masia et al. 2007). This suggests non-genomic pathways through: phosphatidylinositide-3-kinase (Ohashi et al. 2009), calmodulin kinase (Liu et al. 2009b), MAP kinase (Okamoto et al. 2000). "
    05/2015; DOI:10.1530/endoabs.37.GP.17.01
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    • "These nongenomic and genomic mechanisms intersect as a result of MSK1′s phosphorylation of RARa, promoting its capacity to induce gene transcription. Overall, these non-genomic pathways likely provide an important route by which RA has rapid control of cellular events such as neurite outgrowth (Dey et al. 2007), growth cone turning (Farrar et al. 2009) and control of neuronal differentiation (Ca~ n on et al. 2004). "
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    ABSTRACT: The retinoids are a family of compounds that in nature are derived from vitamin A or pro-vitamin A carotenoids. An essential part of the diet for mammals, vitamin A has long been known to be essential for many organ systems in the adult. More recently, however, they have been shown to be necessary for function of the brain and new discoveries point to a central role in processes ranging from neuroplasticity to neurogenesis. Acting in several regions of the central nervous system including the eye, hippocampus and hypothalamus, one common factor in its action is control of biological rhythms. This review summarizes the role of vitamin A in the brain; its action through the metabolite retinoic acid via specific nuclear receptors, and the regulation of its concentration through controlled synthesis and catabolism. The action of retinoic acid to regulate several rhythms in the brain and body, from circadian to seasonal, is then discussed to finish with the importance of retinoic acid in the regular pattern of sleep. We review the role of vitamin A and retinoic acid (RA) as mediators of rhythm in the brain. In the suprachiasmatic nucleus and hippocampus they control expression of circadian clock genes while in the cortex retinoic acid is required for delta oscillations of sleep. Retinoic acid is also central to a second rhythm that keeps pace with the seasons, regulating function in the hypothalamus and pineal gland.
    Journal of Neurochemistry 11/2013; 129(3). DOI:10.1111/jnc.12620 · 4.24 Impact Factor
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    • "This is a novelty in the field of the non-genomic effects of RA and is in agreement with the well-known role of Gaq in the activation of the p38MAPK pathway (Sugawara et al., 2007; White et al., 2008; Mizuno and Itoh, 2009). It is worth noting that this pathway was activated by RA in epithelial and fibroblastic cells but not in neuronal and sertoli cells, where RA rather activates the p42/p44MAPK (Erk) pathway through Src and PI3K (Pan et al., 2005; Dey et al., 2007; Masia et al., 2007; Chen and Napoli, 2008; Zanotto-Filho et al., 2008). Thus, the mechanism of the non-genomic effects of RA appears to involve different membrane-associated complexes, depending on the MAPK pathway that is RA-activated and on the cell type. "
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    ABSTRACT: Retinoic acid (RA) regulates several gene programs by nuclear RA receptors (RARs) that are ligand-dependent transcriptional transregulators. The basic mechanism for switching on transcription of cognate-target genes involves RAR binding at specific response elements and a network of interactions with coregulatory protein complexes. In addition to these classical genomic effects, we recently demonstrated that RA also induces the rapid activation of the p38MAPK/MSK1 pathway, with characteristic downstream consequences on the phosphorylation of RARs and the expression of their target genes. Here, we aimed at deciphering the underlying mechanism of the rapid non-genomic effects of RA. We highlighted a novel paradigm in which a fraction of the cellular RARα pool is present in membrane lipid rafts, where it forms complexes with G protein alpha Q (Gαq) in response to RA. This rapid RA-induced formation of RARα/Gαq complexes in lipid rafts is required for the activation of p38MAPK that occurs in response to RA. Accordingly, in RA-resistant cancer cells, characterized by the absence of p38MAPK activation, RARα present in membrane lipid rafts does not associate with Gαq, pointing out the essential contribution of RARα/Gαq complexes in RA signaling.
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