PMID- 37108437 OWN - NLM STAT- MEDLINE DCOM- 20231028 LR - 20231028 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 24 IP - 8 DP - 2023 Apr 14 TI - Placental Remote Control of Fetal Metabolism: Trophoblast mTOR Signaling Regulates Liver IGFBP-1 Phosphorylation and IGF-1 Bioavailability. LID - 10.3390/ijms24087273 [doi] LID - 7273 AB - The mechanisms mediating the restricted growth in intrauterine growth restriction (IUGR) remain to be fully established. Mechanistic target of rapamycin (mTOR) signaling functions as a placental nutrient sensor, indirectly influencing fetal growth by regulating placental function. Increased secretion and the phosphorylation of fetal liver IGFBP-1 are known to markedly decrease the bioavailability of IGF-1, a major fetal growth factor. We hypothesized that an inhibition of trophoblast mTOR increases liver IGFBP-1 secretion and phosphorylation. We collected conditioned media (CM) from cultured primary human trophoblast (PHT) cells with a silenced RAPTOR (specific inhibition of mTOR Complex 1), RICTOR (inhibition of mTOR Complex 2), or DEPTOR (activates both mTOR Complexes). Subsequently, HepG2 cells, a well-established model for human fetal hepatocytes, were cultured in CM from PHT cells, and IGFBP-1 secretion and phosphorylation were determined. CM from PHT cells with either mTORC1 or mTORC2 inhibition caused the marked hyperphosphorylation of IGFBP-1 in HepG2 cells as determined by 2D-immunoblotting while Parallel Reaction Monitoring-Mass Spectrometry (PRM-MS) identified increased dually phosphorylated Ser169 + Ser174. Furthermore, using the same samples, PRM-MS identified multiple CK2 peptides coimmunoprecipitated with IGFBP-1 and greater CK2 autophosphorylation, indicating the activation of CK2, a key enzyme mediating IGFBP-1 phosphorylation. Increased IGFBP-1 phosphorylation inhibited IGF-1 function, as determined by the reduced IGF-1R autophosphorylation. Conversely, CM from PHT cells with mTOR activation decreased IGFBP-1 phosphorylation. CM from non-trophoblast cells with mTORC1 or mTORC2 inhibition had no effect on HepG2 IGFBP-1 phosphorylation. Placental mTOR signaling may regulate fetal growth by the remote control of fetal liver IGFBP-1 phosphorylation. FAU - Rosario, Fredrick J AU - Rosario FJ AD - Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. FAU - Chopra, Anand AU - Chopra A AD - Institute of Biochemistry, Carleton University, Ottawa, ON K1S 5B6, Canada. FAU - Biggar, Kyle AU - Biggar K AD - Institute of Biochemistry, Carleton University, Ottawa, ON K1S 5B6, Canada. FAU - Powell, Theresa L AU - Powell TL AD - Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. AD - Section of Neonatology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. AD - Department of Biochemistry, University of Western Ontario, London, ON N6A 3K7, Canada. FAU - Gupta, Madhulika B AU - Gupta MB AUID- ORCID: 0000-0001-9197-0341 AD - Department of Biochemistry, University of Western Ontario, London, ON N6A 3K7, Canada. AD - Department of Pediatrics, University of Western Ontario, London, ON N6A 3K7, Canada. AD - Children's Health Research Institute, University of Western Ontario, London, ON N6A 3K7, Canada. FAU - Jansson, Thomas AU - Jansson T AD - Division of Reproductive Sciences, Department of Obstetrics and Gynecology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. LA - eng GR - R01 HD068370/HD/NICHD NIH HHS/United States GR - R01 HD089980/HD/NICHD NIH HHS/United States GR - R21 HD071306/HD/NICHD NIH HHS/United States GR - HD071306, HD089980 and HD068370./HD/NICHD NIH HHS/United States PT - Journal Article DEP - 20230414 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - EC 2.7.1.1 (DEPTOR protein, human) RN - 0 (Insulin-Like Growth Factor Binding Protein 1) RN - 67763-96-6 (Insulin-Like Growth Factor I) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - 0 (IGFBP1 protein, human) RN - 0 (IGF1 protein, human) SB - IM MH - Female MH - Humans MH - Pregnancy MH - Biological Availability MH - Insulin-Like Growth Factor Binding Protein 1/metabolism MH - *Insulin-Like Growth Factor I/metabolism MH - Intracellular Signaling Peptides and Proteins/metabolism MH - Liver/metabolism MH - Mechanistic Target of Rapamycin Complex 1/metabolism MH - Mechanistic Target of Rapamycin Complex 2/metabolism MH - Phosphorylation MH - *Placenta/metabolism MH - TOR Serine-Threonine Kinases/metabolism PMC - PMC10138459 OTO - NOTNLM OT - casein kinase CK2 OT - fetal growth retardation OT - human OT - pregnancy COIS- The authors declare no conflict of interest. EDAT- 2023/04/28 06:41 MHDA- 2023/05/01 06:42 PMCR- 2023/04/14 CRDT- 2023/04/28 01:27 PHST- 2023/02/21 00:00 [received] PHST- 2023/04/02 00:00 [revised] PHST- 2023/04/06 00:00 [accepted] PHST- 2023/05/01 06:42 [medline] PHST- 2023/04/28 06:41 [pubmed] PHST- 2023/04/28 01:27 [entrez] PHST- 2023/04/14 00:00 [pmc-release] AID - ijms24087273 [pii] AID - ijms-24-07273 [pii] AID - 10.3390/ijms24087273 [doi] PST - epublish SO - Int J Mol Sci. 2023 Apr 14;24(8):7273. doi: 10.3390/ijms24087273.