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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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    • "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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    • "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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