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Rapid, Nongenomic Actions of Retinoic Acid on Phosphatidylinositol-3-Kinase Signaling Pathway Mediated by the Retinoic Acid Receptor

Biology of Hormone Action Unit (S.M., D.B.). Department of Molecular and Cellular Pathology and Therapy, Instituto de Biomedicina de Valencia [Consejo Superior de Investigaciones Cientificas (CSIC)], E-46010 Valencia, Spain; Universidade de Vigo (S.A., A.R.d.L.), Departamento de Química Orgánica, Facultad de Ciencias, E-36200 Vigo, Spain

Address all correspondence and requests for reprints to: Dr. Domingo Barettino, Instituto de Biomedicina de Valencia (Consejo Superior de Investigaciones Cientificas). Jaime Roig, 11, E-46010 Valencia, Spain. E-mail: dbarettino{at}ibv.csic.es.

Retinoic acid (RA) treatment of SH-SY5Y neuroblastoma cells results in activation of phosphatidylinositol-3-kinase (PI3K) signaling pathway, and this activation is required for RA-induced differentiation. Here we show that RA activates PI3K and ERK1/2 MAPK signaling pathways through a rapid, nongenomic mechanism that does not require new gene transcription or newly synthesized proteins. Activation of PI3K by RA appears to involve the classical nuclear receptor, retinoic acid receptor (RAR), on the basis of the pharmacological profile of the activation, loss, and gain of function experiments with mouse embryo fibroblast-RAR(ß)^L–/L– null cells, and the physical association between liganded RAR and PI3K activity. The association of RAR with the two subunits of PI3K was differentially regulated by the ligand. Immunoprecipitation experiments performed in SH-SY5Y cells showed stable association between RAR and p85, the regulatory subunit of PI3K, independently of the presence of RA. In contrast, ligand administration increased the association of p110, the catalytic subunit of PI3K, to this complex. The intracellular localization of RAR proved to be relevant for PI3K activation. A chimerical RAR fusing c-Src myristylation domain to the N terminus of RAR (Myr-RAR) was targeted to plasma membrane. Transfection of Myr-RAR to mouse embryo fibroblast-RAR(ß)^L–/L– null cells and COS-7 cells results in strong activation of the PI3K signaling pathway, although both in the absence as well in the presence of RA. Our results support a mechanism in which ligand binding to RAR would play a major role in the assembly and intracellular location of a signaling complex involving RAR and the subunits of PI3K.

NURSA Molecule Pages Link:

Nuclear Receptors:   RARα  |  RARβ  |  RARγ

Coregulators:   CAV1

Ligands:   Am 580  |  all-trans-Retinoic acid  |  9-cis-Retinoic acid  |  Arotinoid acid

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