title: Regulation of the RAP1/RAF-1/extracellularly regulated kinase-1/2 cascade and prolactin release by the phosphoinositide 3-kinase/AKT pathway in pituitary cells.
abstract: In pituitary cells, prolactin (PRL) synthesis and release are controlled by multiple transduction pathways. In the GH4C1 somatolactotroph cell line, we previously reported that MAPK ERK-1/2 are a point of convergence between the pathways involved in the PRL gene regulation. In the present study, we focused on the involvement of the phosphoinositide 3-kinase (PI3K)/Akt pathway in the MAPK ERK-1/2 regulation and PRL secretion in pituitary cells. Either specific pharmacological PI3K and Akt inhibitors (LY294002, Akt I, and phosphoinositide analog-6) or Akt dominant-negative mutant (K179M) enhanced ERK-1/2 phosphorylation in unstimulated GH4C1 cells. Under the same conditions, PI3K and Akt inhibition also both increased Raf-1 kinase activity and the levels of GTP-bound (active form) monomeric G protein Rap1, which suggests that a down-regulation of the ERK-1/2 cascade is induced by the PI3K/Akt signaling pathway in unstimulated cells. On the contrary, ERK-1/2 phosphorylation, Raf-1 activity, and Rap1 activation were almost completely blocked in IGF-I-stimulated cells previously subjected to PI3K or Akt inhibition. Although the PRL promoter was not affected by either PI3K/Akt inhibition or activation, PRL release increased in response to the pharmacological PI3K/Akt inhibitors in unstimulated GH4C1 and rat pituitary primary cells. The IGF-I-stimulated PRL secretion was diminished, on the contrary, by the pharmacological PI3K/Akt inhibitors. Taken together, these findings indicate that the PI3K/Akt pathway exerts dual regulatory effects on both the Rap1/Raf-1/ERK-1/2 cascade and PRL release in pituitary cells, i.e. negative effects in unstimulated cells and positive ones in IGF-I-stimulated cells.
authors.affiliation: Laboratoire Interactions Cellulaires Neuroendocriniennes, Unité Mixte de Recherche 6544, Institut Fédératif de Recherche Jean-Roche, Faculté de Médecine Nord, 13916 Marseille cedex 20, France. romano.d@nord.univ-mrs.fr
authors.forename: David
authors.initials: D
authors.lastname: Romano
authors.forename: Morgane
authors.initials: M
authors.lastname: Pertuit
authors.forename: Ramahefarizo
authors.initials: R
authors.lastname: Rasolonjanahary
authors.forename: Jean-Vianney
authors.initials: JV
authors.lastname: Barnier
authors.forename: Karine
authors.initials: K
authors.lastname: Magalon
authors.forename: Alain
authors.initials: A
authors.lastname: Enjalbert
authors.forename: Corinne
authors.initials: C
authors.lastname: Gerard
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005260:Female; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D010902:Pituitary Gland / Q000166:cytology / Q000378:metabolism; D011388:Prolactin / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D020239:Receptor Cross-Talk; D015398:Signal Transduction; D052683:Somatotrophs / Q000378:metabolism*; D015533:Transcriptional Activation; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
chemical_list: D011388:Prolactin; D019869:Phosphatidylinositol 3-Kinases; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020827:rap1 GTP-Binding Proteins; D018631:ras Proteins