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Growth differentiation factor-9 signaling is mediated by the type I receptor, activin receptor-like kinase 5 Mazerbourg S; Klein C; Roh J; Kaivo-Oja N; Mottershead DG; Korchynskyi O; Ritvos O; Hsueh AJMol Endocrinol 2004[Mar]; 18 (3): 653-65Growth differentiation factor-9 (GDF-9) is an oocyte-derived growth factor and a member of the TGF-beta superfamily that includes TGF-beta, 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-beta 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-beta 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-beta, diverse members of the TGF-beta family of ligands appear to interact with a limited number of receptors in a combinatorial manner to activate two downstream Smad pathways.|*Smad2 Protein[MESH]|Activin Receptors, Type I/drug effects/genetics/*metabolism[MESH]|Activin Receptors/drug effects/genetics/*metabolism[MESH]|Activins/metabolism/pharmacology[MESH]|Animals[MESH]|Bone Morphogenetic Protein 15[MESH]|Bone Morphogenetic Proteins/metabolism[MESH]|COS Cells/drug effects/metabolism[MESH]|Cells, Cultured[MESH]|DNA-Binding Proteins/drug effects/genetics/metabolism[MESH]|Female[MESH]|Granulosa Cells/drug effects/metabolism[MESH]|Growth Differentiation Factor 9[MESH]|Intercellular Signaling Peptides and Proteins/*metabolism/pharmacology[MESH]|Phosphorylation[MESH]|Promoter Regions, Genetic[MESH]|Protein Serine-Threonine Kinases[MESH]|RNA, Small Interfering[MESH]|Rats[MESH]|Rats, Sprague-Dawley[MESH]|Receptor, Transforming Growth Factor-beta Type I[MESH]|Receptors, Transforming Growth Factor beta/drug effects/genetics/*metabolism[MESH]|Signal Transduction[MESH]|Smad Proteins[MESH]|Smad3 Protein[MESH]|Smad6 Protein[MESH]|Smad7 Protein[MESH]|Trans-Activators/drug effects/genetics/metabolism[MESH]|Transforming Growth Factor beta/metabolism/pharmacology[MESH] |
