{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T19:24:49Z","timestamp":1791228289484,"version":"4.1.0"},"reference-count":35,"publisher":"Portland Press Ltd.","issue":"12","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2015,12,1]]},"abstract":"<jats:p>Placental amino acid transport is decreased in intrauterine growth restriction (IUGR); however, the underlying mechanisms remain largely unknown. We have shown that mechanistic target of rapamycin (mTOR) signalling regulates system A amino acid transport by modulating the ubiquitination and plasma membrane trafficking of sodium-coupled neutral amino acid transporter 2 (SNAT-2) in cultured primary human trophoblast cells. We hypothesize that IUGR is associated with (1) inhibition of placental mTORC1 and mTORC2 signalling pathways, (2) increased amino acid transporter ubiquitination in placental homogenates and (3) decreased protein expression of SNAT-2\u00a0in the syncytiotrophoblast microvillous plasma membrane (MVM). To test this hypothesis, we collected placental tissue and isolated MVM from women with pregnancies complicated by IUGR (n=25) and gestational age-matched women with appropriately grown control infants (n=19, birth weights between the twenty-fifth to seventy-fifth percentiles). The activity of mTORC1 and mTORC2 was decreased whereas the protein expression of the ubiquitin ligase NEDD4-2 (neural precursor cell expressed developmentally down-regulated protein 4-2; +72%, P&amp;lt;0.0001) and the ubiquitination of SNAT-2 (+180%, P&amp;lt;0.05) were increased in homogenates of IUGR placentas. Furthermore, IUGR was associated with decreased system A amino acid transport activity (\u201372%, P&amp;lt;0.0001) and SNAT-1 (\u201342%, P&amp;lt;0.05) and SNAT-2 (\u201331%, P&amp;lt;0.05) protein expression in MVM. In summary, these findings are consistent with the possibility that decreased placental mTOR activity causes down-regulation of placental system A activity by shifting SNAT-2 trafficking towards proteasomal degradation, thereby contributing to decreased fetal amino acid availability and restricted fetal growth in IUGR.<\/jats:p>","DOI":"10.1042\/cs20150511","type":"journal-article","created":{"date-parts":[[2015,9,15]],"date-time":"2015-09-15T21:39:51Z","timestamp":1442353191000},"page":"1131-1141","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":91,"title":["Increased ubiquitination and reduced plasma membrane trafficking of placental amino acid transporter SNAT-2\u00a0in human IUGR"],"prefix":"10.1042","volume":"129","author":[{"given":"Yi-Yung","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Obstetrics & Gynecology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, U.S.A."},{"name":"Division of High-risk Pregnancy, Department of Obstetrics & Gynecology, Mackay Memorial Hospital, Taipei 10449, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fredrick\u00a0J.","family":"Rosario","sequence":"additional","affiliation":[{"name":"Department of Obstetrics & Gynecology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Majida\u00a0Abu","family":"Shehab","sequence":"additional","affiliation":[{"name":"Children's Health Research Institute, University of Western Ontario, London, Ontario N6C 2V5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theresa\u00a0L.","family":"Powell","sequence":"additional","affiliation":[{"name":"Department of Obstetrics & Gynecology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, U.S.A."},{"name":"Department of Pediatrics, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madhulika\u00a0B.","family":"Gupta","sequence":"additional","affiliation":[{"name":"Children's Health Research Institute, University of Western Ontario, London, Ontario N6C 2V5, Canada"},{"name":"Department of Pediatrics and Biochemistry, University of Western Ontario, London, Ontario N6A 5C1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Jansson","sequence":"additional","affiliation":[{"name":"Department of Obstetrics & Gynecology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, U.S.A."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2015,10,22]]},"reference":[{"key":"2021113010554512200_B1","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1016\/j.jpeds.2010.05.002","article-title":"Impact of fetal growth restriction on mortality and morbidity in a very preterm birth cohort","volume":"157","author":"Zeitlin","year":"2010","journal-title":"J. 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