{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T11:16:18Z","timestamp":1780917378086,"version":"3.54.1"},"reference-count":84,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,9,18]],"date-time":"2021-09-18T00:00:00Z","timestamp":1631923200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HD089980"],"award-info":[{"award-number":["R01HD089980"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Insulin-like growth factor-1 (IGF-1) bioavailability in pregnancy is governed by IGF binding protein (IGFBP-1) and its phosphorylation, which enhances the affinity of IGFBP-1 for the growth factor. The decidua is the predominant source of maternal IGFBP-1; however, the mechanisms regulating decidual IGFBP-1 secretion\/phosphorylation are poorly understood. Using decidualized primary human endometrial stromal cells (HESCs) from first-trimester placenta, we tested the hypothesis that mTORC1 signaling mechanistically links hypoxia to decidual IGFBP-1 secretion\/phosphorylation. Hypoxia inhibited mechanistic target of rapamycin (mTORC1) (p-P70-S6K\/Thr389, \u221247%, p = 0.038; p-4E-BP1\/Thr70, \u221255%, p = 0.012) and increased IGFBP-1 (total, +35%, p = 0.005; phosphorylated, Ser101\/+82%, p = 0.018; Ser119\/+88%, p = 0.039; Ser 169\/+157%, p = 0.019). Targeted parallel reaction monitoring-mass spectrometry (PRM-MS) additionally demonstrated markedly increased dual IGFBP-1 phosphorylation (pSer98+Ser101; pSer169+Ser174) in hypoxia. IGFBP-1 hyperphosphorylation inhibited IGF-1 receptor autophosphorylation\/ Tyr1135 (\u221229%, p = 0.002). Furthermore, silencing of tuberous sclerosis complex 2 (TSC2) activated mTORC1 (p-P70-S6K\/Thr389, +68%, p = 0.038; p-4E-BP1\/Thr70, +30%, p = 0.002) and reduced total\/site-specific IGFBP-1 phosphorylation. Importantly, TSC2 siRNA prevented inhibition of mTORC1 and the increase in secretion\/site-specific IGFBP-1 phosphorylation in hypoxia. PRM-MS indicated concomitant changes in protein kinase autophosphorylation (CK2\/Tyr182; PKC\/Thr497; PKC\/Ser657). Overall, mTORC1 signaling mechanistically links hypoxia to IGFBP-1 secretion\/phosphorylation in primary HESC, implicating decidual mTORC1 inhibition as a novel mechanism linking uteroplacental hypoxia to fetal growth restriction.<\/jats:p>","DOI":"10.3390\/biom11091382","type":"journal-article","created":{"date-parts":[[2021,9,20]],"date-time":"2021-09-20T07:52:14Z","timestamp":1632124334000},"page":"1382","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Mechanistic Target of Rapamycin Complex 1 Signaling Links Hypoxia to Increased IGFBP-1 Phosphorylation in Primary Human Decidualized Endometrial Stromal Cells"],"prefix":"10.3390","volume":"11","author":[{"given":"Pinki","family":"Nandi","sequence":"first","affiliation":[{"name":"Departments of Pediatrics, University of Western Ontario, London, ON N6A 5C1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chloe E.","family":"Jang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, University of Western Ontario, London, ON N6A 5C1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle","family":"Biggar","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry and Department of Biology, Carleton University, Ottawa, ON K1S 5B6, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chidambra D.","family":"Halari","sequence":"additional","affiliation":[{"name":"Departments of Anatomy and Cell Biology, University of Western Ontario, London, ON N6A 3K7, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Jansson","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Division of Reproductive Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madhulika B.","family":"Gupta","sequence":"additional","affiliation":[{"name":"Departments of Pediatrics, University of Western Ontario, London, ON N6A 5C1, Canada"},{"name":"Department of Biochemistry, University of Western Ontario, London, ON N6A 5C1, Canada"},{"name":"Children\u2019s Health Research Institute, London, ON N6C 2V5, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1097\/00003081-200606000-00008","article-title":"Perinatal Outcome and Later Implications of Intrauterine Growth Restriction","volume":"49","author":"Pallotto","year":"2006","journal-title":"Clin. 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