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CSK controls retinoic acid receptor (RAR) signaling: a RAR-c-SRC signaling axis is required for neuritogenic differentiation.
Dey, Nandini; De, Pradip K; Wang, Mu; Zhang, Hongying; Dobrota, Erika A; Robertson, Kent A; Durden, Donald L.
Afiliación
  • Dey N; 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.
Mol Cell Biol ; 27(11): 4179-97, 2007 Jun.
Article en En | MEDLINE | ID: mdl-17325034
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.
Asunto(s)

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Proteínas Tirosina Quinasas / Transducción de Señal / Diferenciación Celular / Genes src / Proteínas Proto-Oncogénicas pp60(c-src) / Neuritas / Receptores de Ácido Retinoico Límite: Animals / Humans Idioma: En Revista: Mol Cell Biol Año: 2007 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Proteínas Tirosina Quinasas / Transducción de Señal / Diferenciación Celular / Genes src / Proteínas Proto-Oncogénicas pp60(c-src) / Neuritas / Receptores de Ácido Retinoico Límite: Animals / Humans Idioma: En Revista: Mol Cell Biol Año: 2007 Tipo del documento: Article País de afiliación: Estados Unidos