ArticleClinical science (London, England : 1979)2016
Regulation of amino acid transporter trafficking by mTORC1 in primary human trophoblast cells is mediated by the ubiquitin ligase Nedd4-2.
Article in Clinical science (London, England : 1979), 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 71 papers.
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Who cites it
71 citing papers in PubMed, 104 citations in OpenAlex.
- Understanding physiological adaptations of pregnancy to the chronic hypoxia of high altitude to inform obstetrical and neonatal care.Physiological reviews · 2026Review
- Sexual Dimorphism in Placental mTORC1 Signaling, Amino Acid Transport, and Mitochondrial Respiration at Term.Antioxidants (Basel, Switzerland) · 2026Article
- Nutritional restriction during late gestation disrupts placental transcriptional programs related to metabolism, transport, and immune function in a sheep model.BMC genomics · 2026Article
- Amino Acid Dysregulation in the Mother-Fetus Unit: Multi-Compartment Metabolomic Signatures of Gestational Diabetes Mellitus and Fetal Macrosomia.International journal of molecular sciences · 2026Article
- Inducible trophoblast-specific knockdown of mechanistic target of rapamycin impairs placental folate transport in mice.The Journal of nutritional biochemistry · 2026Article
- Unraveling the complex web: pathogenesis and prevention of gestational diabetes mellitus-related fetal overgrowth.Frontiers in cell and developmental biology · 2026Review
- TXNIP mediates LAT1/SLC7A5 endocytosis to limit amino acid uptake in cells entering quiescence.The EMBO journal · 2025Article
- Novel role for PI3Kβ in placental function through regulation of system A amino acid transporter expression, associated with embryonic lethality.Cellular and molecular life sciences : CMLS · 2025Article
- Normalization of trophoblast mTOR signaling rescues impaired function in primary human trophoblast cells isolated from pregnancies complicated by fetal growth restriction.Cell death discovery · 2025Article
- PiggyBac transposase-mediated inducible trophoblast-specific knockdown of Mtor decreases placental nutrient transport and fetal growth.Clinical science (London, England : 1979) · 2025Article
- Trophoblast-specific Deptor knockdown enhances trophoblast nutrient transport and fetal growth in mice.Acta physiologica (Oxford, England) · 2025Article
- Lentivirus-Mediated Trophoblast-Specific Deptor Knockdown Increases Transplacental System A and System L Amino Acid Transport and Fetal Growth in Mice.Function (Oxford, England) · 2025Article
- Mechanistic target of rapamycin signaling activity in the human placenta across gestation and in maternal obesity†.Biology of reproduction · 2025Article
- Regulation of placental amino acid transport in health and disease.Acta physiologica (Oxford, England) · 2024Review
- Trophoblast-specific overexpression of the LAT1 increases transplacental transport of essential amino acids and fetal growth in mice.PNAS nexus · 2024Article
- Placental transcriptomic signatures of prenatal and preconceptional maternal stress.Molecular psychiatry · 2024Article
- Oleic acid stimulation of amino acid uptake in primary human trophoblast cells is mediated by phosphatidic acid and mTOR signaling.FASEB bioAdvances · 2024Article
- Overexpression of the LAT1 in primary human trophoblast cells increases the uptake of essential amino acids and activates mTOR signaling.Clinical science (London, England : 1979) · 2023Article
- CHOP upregulation and dysregulation of the mature form of the SNAT2 amino acid transporter in the placentas from small for gestational age newborns.Cell communication and signaling : CCS · 2023Article
- Maternal-fetal cross-talk via the placenta: influence on offspring development and metabolism.Development (Cambridge, England) · 2023Review
11 more citing papers are in PubMed but not listed here.
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5 authors at 2 institutions in 2 countries.
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Abstract
Changes in placental amino acid transfer directly contribute to altered fetal growth, which increases the risk for perinatal complications and predisposes for the development of obesity, diabetes and cardiovascular disease later in life. Placental amino acid transfer is critically dependent on the expression of specific transporters in the plasma membrane of the trophoblast, the transporting epithelium of the human placenta. However, the molecular mechanisms regulating this process are largely unknown. Nedd4-2 is an ubiquitin ligase that catalyses the ubiquitination of proteins, resulting in proteasomal degradation. We hypothesized that inhibition of mechanistic target of rapamycin complex 1 (mTORC1) decreases amino acid uptake in primary human trophoblast (PHT) cells by activation of Nedd4-2, which increases transporter ubiquitination resulting in decreased transporter expression in the plasma membrane. mTORC 1 inhibition increased the expression of Nedd4-2, promoted ubiquitination and decreased the plasma membrane expression of SNAT2 (an isoform of the System A amino acid transporter) and LAT1 (a System L amino acid transporter isoform), resulting in decreased cellular amino acid uptake. Nedd4-2 silencing markedly increased the trafficking of SNAT2 and LAT1 to the plasma membrane, which stimulated cellular amino acid uptake. mTORC1 inhibition by silencing of raptor failed to decrease amino acid transport following Nedd4-2 silencing. In conclusion, we have identified a novel link between mTORC1 signalling and ubiquitination, a common posttranslational modification. Because placental mTORC1 is inhibited in fetal growth restriction and activated in fetal overgrowth, we propose that regulation of placental amino acid transporter ubiquitination by mTORC1 and Nedd4-2 constitutes a molecular mechanisms underlying abnormal fetal growth.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.