Down-regulation of the phosphatidylinositol 3-kinase/Akt pathway is involved in retinoic acid-induced phosphorylation, degradation, and transcriptional activity of retinoic acid receptor gamma 2.
Nuclear retinoic acid (RA) receptors (RARs) are phosphorylated at conserved serine residues located in their N-terminal domain. Phosphorylation of RARgamma2 at these residues is increased in response to RA subsequently to the activation of p38MAPK. We show here that this RA-induced phosphorylation of RARgamma2 resulted from the down-regulation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. By overexpressing Akt and by using agents that activated or inhibited the PI3K/Akt pathway, we also demonstrated that the RA-induced down-regulation of the PI3K/Akt pathway targeted not only the phosphorylation of RARgamma2 but also the turnover and transcriptional activity of the receptor. Altogether these data indicate that the PI3K/Akt pathway plays an important role in retinoic acid signaling.
Gianni
Maurizio
M
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université Louis Pasteur/Collège de France, BP 163, 67404 Illkirch Cedex, France.
Kopf
Eliezer
E
Bastien
Julie
J
Oulad-Abdelghani
Mustapha
M
Garattini
Enrico
E
Chambon
Pierre
P
Rochette-Egly
Cecile
C
D000818:Animals; D002460:Cell Line; D015536:Down-Regulation; D004789:Enzyme Activation; D006868:Hydrolysis; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D018168:Receptors, Retinoic Acid / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects* / Q000502:physiology; D014212:Tretinoin / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases; D000097768:Retinoic Acid Receptor gamma
D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D018168:Receptors, Retinoic Acid; D014212:Tretinoin; D048051:p38 Mitogen-Activated Protein Kinases; D000097768:Retinoic Acid Receptor gamma