1. 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
- Author
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Morgane Pertuit, David Romano, Ramahefarizo Rasolonjanahary, Jean-Vianney Barnier, Karine Magalon, Corinne Gerard, Alain Enjalbert, Interactions cellulaires neuroendocriniennes (ICN), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Laboratoire de neurobiologie cellulaire et moléculaire (NBCM), Centre National de la Recherche Scientifique (CNRS), and Institut de Neurobiologie Alfred Fessard (INAF)
- Subjects
MAPK/ERK pathway ,GH4C1 cell line ,Proto-Oncogene Proteins B-raf ,Transcriptional Activation ,medicine.medical_specialty ,endocrine system ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,chemistry.chemical_compound ,Phosphatidylinositol 3-Kinases ,Endocrinology ,prolactin secretion ,Internal medicine ,medicine ,Animals ,LY294002 ,Kinase activity ,Rats, Wistar ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Cells, Cultured ,Ras/Rap1 GTPases ,Mitogen-Activated Protein Kinase 1 ,Mitogen-Activated Protein Kinase 3 ,Akt/PKB signaling pathway ,rap1 GTP-Binding Proteins ,Receptor Cross-Talk ,MAPKinase pathway ,Somatotrophs ,Cell biology ,Prolactin ,Rats ,Proto-Oncogene Proteins c-raf ,chemistry ,pituitary primary cells ,PI3K/Akt pathway ,Pituitary Gland ,ras Proteins ,Phosphorylation ,Female ,Signal transduction ,Proto-Oncogene Proteins c-akt ,Signal Transduction - 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.
- Published
- 2006