Cell-specificity of transforming growth factor-β response is dictated by receptor bioavailability

Members of the transforming growth factor- (TGF) family control diverse cellular responses including differentiation, proliferation, controlled cell death and migration. The response of a cell to an individual ligand is highly restricted yet the signaling pathways for TGF, activin and bone morphogenic proteins share a limited number of receptors and activate similar intracellular cytoplasmic co-regulators, Smads. A central question in the study of this family of ligands is how cells titrate and integrate each TGF-like signal in order to respond in a cell- and ligand-specific manner. This study uses the pituitary gonadotrope cell line, LT2, as a model to delineate the relative contribution of TGF and activin ligands to follicle-stimulating hormone (FSH) biosynthesis. It was found that pituitary gonadotrope cells do not express the TGF type II (TRII) receptor and are therefore not responsive to the TGF ligand. Transfection of the receptor restores TGF signaling capabilities and the TGF-mediated stimulation of FSH gene transcription in LT2 cells. Consequently, we evaluated the presence of the TRII in the adult mouse pituitary. TRII does not co-localize with FSH-producing cells; however it is detected on the cell surface of prolactin- and growth hormone-positive cells. Taken together, these results suggest that the bioavailability of the TGF-specific receptor rather than TGF dictates pituitary gonadotrope selectivity to activin, which is necessary to maintain normal reproductive function. It is likely that the ligand-restricted mechanisms employed by the gonadotrope are present in other cells, which could explain the distinct control of many cellular processes by members of the TGF superfamily.