Down-regulation of placental Cdc42 and Rac1 links mTORC2 inhibition to decreased trophoblast amino acid transport in human intrauterine growth restriction
| Autor: | Theresa L. Powell, Thomas Jansson, Marisol Castillo-Castrejon, Fredrick J. Rosario, Madhulika B. Gupta |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
rac1 GTP-Binding Protein
0301 basic medicine congenital hereditary and neonatal diseases and abnormalities Placenta Mechanistic Target of Rapamycin Complex 2 mTORC1 Pediatrics Article 03 medical and health sciences 0302 clinical medicine Syncytiotrophoblast Pregnancy medicine Humans Amino acid transporter cdc42 GTP-Binding Protein Mechanistic target of rapamycin chemistry.chemical_classification Fetal Growth Retardation biology Chemistry Cell Membrane Trophoblast General Medicine Actin cytoskeleton Trophoblasts Cell biology Amino acid 030104 developmental biology medicine.anatomical_structure biology.protein Female 030217 neurology & neurosurgery |
| Zdroj: | Clin Sci (Lond) Paediatrics Publications |
| ISSN: | 1470-8736 0143-5221 |
| Popis: | Intrauterine growth restriction (IUGR) increases the risk for perinatal complications and metabolic and cardiovascular disease later in life. The syncytiotrophoblast (ST) is the transporting epithelium of the human placenta, and decreased expression of amino acid transporter isoforms in the ST plasma membranes is believed to contribute to IUGR. Placental mechanistic target of rapamycin Complex 2 (mTORC2) signaling is inhibited in IUGR and regulates the trafficking of key amino acid transporter (AAT) isoforms to the ST plasma membrane; however, the molecular mechanisms are unknown. Cdc42 and Rac1 are Rho-GTPases that regulate actin-binding proteins, thereby modulating the structure and dynamics of the actin cytoskeleton. We hypothesized that inhibition of mTORC2 decreases AAT expression in the plasma membrane and amino acid uptake in primary human trophoblast (PHT) cells mediated by down-regulation of Cdc42 and Rac1. mTORC2, but not mTORC1, inhibition decreased the Cdc42 and Rac1 expression. Silencing of Cdc42 and Rac1 inhibited the activity of the System L and A transporters and markedly decreased the trafficking of LAT1 (System L isoform) and SNAT2 (System A isoform) to the plasma membrane. mTORC2 inhibition by silencing of rictor failed to decrease AAT following activation of Cdc42/Rac1. Placental Cdc42 and Rac1 protein expression was down-regulated in human IUGR and was positively correlated with placental mTORC2 signaling. In conclusion, mTORC2 regulates AAT trafficking in PHT cells by modulating Cdc42 and Rac1. Placental mTORC2 inhibition in human IUGR may contribute to decreased placental amino acid transfer and reduced fetal growth mediated by down-regulation of Cdc42 and Rac1. |
| Databáze: | OpenAIRE |
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