Differential regulation of mTORC1 and mTORC2 is critical for 8-Br-cAMP-induced decidualization

• Published in: Experimental & molecular medicine 2018, 50(0), , pp.1-11
• Main Authors: Baek, Mi-Ock, Song, Hae-In, Han, Joong-Soo, Yoon, Mee-Sup
• Format: Article
• Language: English
• Subjects: 13; 13/89; 13/95; 14; 14/63; 38; 38/109; 38/77; 42; 631/136/142; 631/80/86/2368; 692/699/2732/1577; 8-Bromo Cyclic Adenosine Monophosphate - metabolism; 82; 96; 96/95; Adult; AKT protein; Biomedical and Life Sciences; Biomedicine; Cyclic AMP; Decidua - metabolism; Endometrium; Female; Forkhead Box Protein O1 - metabolism; Forkhead protein; FOXO1 protein; Humans; Implantation; Insulin; Insulin receptor substrate 1; Insulin Receptor Substrate Proteins - metabolism; Insulin-like growth factor-binding protein 1; Intracellular Signaling Peptides and Proteins - metabolism; Mechanistic Target of Rapamycin Complex 1 - metabolism; Mechanistic Target of Rapamycin Complex 2 - metabolism; Medical Biochemistry; Middle Aged; Molecular Medicine; mRNA; Phosphorylation; Pregnancy; Prolactin; Proto-Oncogene Proteins c-akt - metabolism; Rapamycin; Serine; Stem Cells; Stromal cells; TOR protein; 생화학
• ISSN: 1226-3613; 2092-6413
• DOI: 10.1038/s12276-018-0165-3

Human endometrium decidualization, a differentiation process involving biochemical and morphological changes, is a prerequisite for embryo implantation and successful pregnancy. Here, we show that the mammalian target of rapamycin (mTOR) is a crucial regulator of 8-bromoadenosine 3’,5’-cyclic monophosphate (8-Br-cAMP)-induced decidualization in human endometrial stromal cells. The level of mSin1 in mTOR complex 2 (mTORC2) and DEPTOR in mTOR complex 1 (mTORC1) decreases during 8-Br-cAMP-induced decidualization, resulting in decreased mTORC2 activity and increased mTORC1 activity. Notably, DEPTOR displacement increases the association between raptor and insulin receptor substrate-1 (IRS-1), facilitating IRS-1 phosphorylation at serine 636/639. Finally, both S473 and T308 phosphorylation of Akt are reduced during decidualization, followed by a decrease in forkhead box O1 (FOXO1) phosphorylation and an increase in the mRNA levels of the decidualization markers prolactin (PRL) and insulin-like growth factor-binding protein-1 (IGFBP-1). Taken together, our findings reveal a critical role for mTOR in decidualization, involving the differential regulation of mTORC1 and mTORC2. Fertility: How cells lining the uterus prepare for pregnancy A key signaling pathway plays a critical role in readying cells of the endometrium, the uterine lining, for embryo implantation and pregnancy. Mammalian target of rapamycin (mTOR) is an enzyme that links with other proteins to form two distinct protein complexes that regulate a variety of cellular processes. Researchers in Republic of Korea led by Joong-Soo Han from Hanyang University in Seoul, and Mee-Sup Yoon from Gachon University in Incheon found that levels of certain components within these two complexes decrease in the endometrium as cells change in size and shape in preparation for pregnancy. This process, they showed, also alters the pattern of phosphate groups on the mTOR complexes, ultimately leading to decreased overall activity of mTOR complex 2 but increased activity of mTOR complex 1. The findings could inform future development of fertility treatments.