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https://hdl.handle.net/2440/54920
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Type: | Journal article |
Title: | Growth Differentiation Factor-9 Signaling Is Mediated by the Type I Receptor, Activin Receptor-Like Kinase 5 |
Author: | Mazerbourg, S. Klein, C. Roh, J. Kaivo-Oja, N. Mottershead, D. Korchynskyi, O. Ritvos, O. Hsueh, A. |
Citation: | Molecular Endocrinology, 2004; 18(3):653-665 |
Publisher: | Endocrine Soc |
Issue Date: | 2004 |
ISSN: | 0888-8809 1944-9917 |
Statement of Responsibility: | Sabine Mazerbourg, Cynthia Klein, Jaesook Roh, Noora Kaivo-Oja, David G. Mottershead, Olexander Korchynskyi, Olli Ritvos and Aaron J. W. Hsueh |
Abstract: | Growth differentiation factor-9 (GDF-9) is an oocyte-derived growth factor and a member of the TGF-ß superfamily that includes TGF-ß, activin, and bone morphogenetic proteins (BMPs). GDF-9 is indispensable for the development of ovarian follicles from the primary stage, and treatment with GDF-9 enhances the progression of early follicles into small preantral follicles. Similar to other TGF-ß family ligands, GDF-9 likely initiates signaling mediated by type I and type II receptors with serine/threonine kinase activity, followed by the phosphorylation of intracellular transcription factors named Smads. We have shown previously that GDF-9 interacts with the BMP type II receptor (BMPRII) in granulosa cells, but the type I receptor involved is unknown. Using P19 cells, we now report that GDF-9 treatment stimulated the CAGA-luciferase reporter known to be responsive to TGF-ß mediated by the type I receptor, activin receptor-like kinase (ALK)5. In contrast, GDF-9 did not stimulate BMP-responsive reporters. In addition, treatment with GDF-9 induced the phosphorylation of Smad2 and Smad3 in P19 cells, and the stimulatory effect of GDF-9 on the CAGA-luciferase reporter was blocked by the inhibitory Smad7, but not Smad6. We further reconstructed the GDF-9 signaling pathway using Cos7 cells that are not responsive to GDF-9. After overexpression of ALK5, with or without exogenous Smad3, the Cos7 cells gained GDF-9 responsiveness based on the CAGA-luciferase reporter assay. The roles of ALK5 and downstream pathway genes in mediating GDF-9 actions were further tested in ovarian cells. In cultured rat granulosa cells from early antral follicles, treatment with GDF-9 stimulated the CAGA-luciferase reporter activity and induced the phosphorylation of Smad3. Furthermore, transfection with small interfering RNA for ALK5 or overexpression of the inhibitory Smad7 resulted in dose-dependent suppression of GDF-9 actions. In conclusion, although GDF-9 binds to the BMP-activated type II receptor, its downstream actions are mediated by the type I receptor, ALK5, and the Smad2 and Smad3 proteins. Because ALK5 is a known receptor for TGF-ß, diverse members of the TGF-ß family of ligands appear to interact with a limited number of receptors in a combinatorial manner to activate two downstream Smad pathways. |
DOI: | 10.1210/me.2003-0393 |
Published version: | http://dx.doi.org/10.1210/me.2003-0393 |
Appears in Collections: | Aurora harvest Obstetrics and Gynaecology publications |
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