This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Romano, D. Articles by Gerard, C. Search for Related Content PubMed PubMed Citation Articles by Romano, D. Articles by Gerard, C.

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

Laboratoire Interactions Cellulaires Neuroendocriniennes (D.R., M.P., R.R., K.M., A.E., C.G.), Unité Mixte de Recherche 6544, Institut Fédératif de Recherche Jean-Roche, Faculté de Médecine Nord, 13916 Marseille cedex 20, France; and Laboratoire de Neurobiologie Cellulaire et Moléculaire (J.-V.B.), 91198 Gif-sur-Yvette, France

Address all correspondence and requests for reprints to: David Romano, Laboratoire Interactions Cellulaires Neuroendocriniennes, Unité Mixte de Recherche 6544, Institut Fédératif de Recherche Jean-Roche, Faculté de Médecine Nord, 13916 Marseille cedex 20, France. E-mail: romano.d{at}nord.univ-mrs.fr.

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.

This article has been cited by other articles:

				N. J. MacLaine, M. D. Wood, J. C. Holder, R. W. Rees, and J. Southgate Sensitivity of Normal, Paramalignant, and Malignant Human Urothelial Cells to Inhibitors of the Epidermal Growth Factor Receptor Signaling Pathway Mol. Cancer Res., January 1, 2008; 6(1): 53 - 63. [Abstract] [Full Text] [PDF]

				C.-C. Su, Y.-P. Lin, Y.-J. Cheng, J.-Y. Huang, W.-J. Chuang, Y.-S. Shan, and B.-C. Yang Phosphatidylinositol 3-Kinase/Akt Activation by Integrin-Tumor Matrix Interaction Suppresses Fas-Mediated Apoptosis in T Cells J. Immunol., October 1, 2007; 179(7): 4589 - 4597. [Abstract] [Full Text] [PDF]