CSK controls Retinoic Acid Receptor (RAR) signaling: A RAR-c-SRC signaling axis is required for neuritogenic differentiation

Nandini Dey, Pradip K. De, Mu Wang, Hongying Zhang, Erika A. Dobrota, Kent A. Robertson, Donald L. Durden

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

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 RARγ 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 RARγ to c-SRC. Deletion of a proline-rich domain within RARγ 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.

Original languageEnglish (US)
Pages (from-to)4179-4197
Number of pages19
JournalMolecular and cellular biology
Volume27
Issue number11
DOIs
StatePublished - Jun 2007

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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