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Molecular and Cellular Biology, June 2007, p. 4179-4197, Vol. 27, No. 11
0270-7306/07/$08.00+0     doi:10.1128/MCB.01352-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

CSK Controls Retinoic Acid Receptor (RAR) Signaling: a RAR-c-SRC Signaling Axis Is Required for Neuritogenic Differentiation{triangledown}

Nandini Dey,1 Pradip K. De,1 Mu Wang,2 Hongying Zhang,1 Erika A. Dobrota,3 Kent A. Robertson,3* and Donald L. Durden1*

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, Georgia 30022,1 Department of Pediatrics, Wells Center for Pediatrics Research, Riley Hospital for Children, Indiana University Medical Center, Indianapolis, Indiana 46202,3 Department of Biochemistry and Molecular Biology, School of Medicine, Indiana University, Indianapolis, Indiana 462022

Received 24 July 2006/ Returned for modification 12 September 2006/ Accepted 14 February 2007

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 RAR{gamma} 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 RAR{gamma} to c-SRC. Deletion of a proline-rich domain within RAR{gamma} 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.

* Corresponding author. Mailing address for Donald L. Durden: 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. Phone: (404) 778-5069. Fax: (404) 727-4455. E-mail: don_durden{at}oz.ped.emory.edu. Mailing address for Kent A. Robertson: Department of Pediatrics, Wells Center for Pediatrics Research, Riley Hospital for Children, Indiana University Medical Center, Indianapolis, IN 46202. Phone: (317) 274-0991. Fax: (317) 278-9298. E-mail: krobertson{at}iupui.edu

{triangledown} Published ahead of print on 26 February 2007.

Molecular and Cellular Biology, June 2007, p. 4179-4197, Vol. 27, No. 11
0270-7306/07/$08.00+0     doi:10.1128/MCB.01352-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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