mTOR: a placental growth signaling sensor.

The proliferation and differentiation of trophoblast cells is under the control of a variety of hormones and growth factors and is influenced by nutrient availability. The intracellular signaling pathways acting downstream of these mitogenic factors and nutrients to regulate trophoblast proliferation and placental development are poorly understood. Immortalized human trophoblast cells were used (HTR-8/SVneo) to investigate trophoblast proliferation in response to angiopoietin-2 (Ang-2), a major angiogenic factor and glucose (a major nutrient). Trophoblast cell proliferation was induced through activation of the phosphatidylinositol-3 (PI-3) kinase and the mammalian target of rapamycin (mTOR) signaling pathways, following Tie-2 receptor activation. Glucose also stimulated trophoblast cell proliferation through mTOR signaling. Ang-2 activated mTOR via PI-3 kinase-dependent signaling; whereas glucose-mediated mTOR activation was PI-3 kinase-independent and involved a novel nutrient sensor, glutamine fructose-6-phosphate amidotransferase (GFAT). Metabolites of the GFAT reaction acted upstream of mTOR and functioned as a nutrient sensor to regulate trophoblast cell proliferation in response to glucose. Overall, the results show that growth factor and nutrient signaling converge at tuberin, an upstream regulator of mTOR and that mTOR functions as an important placental growth signaling sensor. These results are the first to link mTOR with GFAT metabolites as nutrient sensors for trophoblast cell proliferation.