NCBI Summary:
RICTOR and MTOR (FRAP1; MIM 601231) are components of a protein complex that integrates nutrient- and growth factor-derived signals to regulate cell growth (Sarbassov et al., 2004 [PubMed 15268862]).[supplied by OMIM, Mar 2008]
General function
Intracellular signaling cascade
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Cellular localization
Cytoplasmic
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Ovarian function
Antral follicle growth, Oocyte maturation
Comment
Distribution and association of mTOR with its cofactors, raptor and rictor, in cumulus cells and oocytes during meiotic maturation in mice. Kogasaka Y et al. Mammalian target of rapamycin (mTOR), a Ser/Thr protein kinase, is the catalytic component of 2 distinct signaling complexes, mTOR-raptor complex (mTORC1) and mTOR-rictor complex (mTORC2). Recently, studies have demonstrated mitosis-specific roles for mTORC1, but the functions and expression dynamics of mTOR complexes during meiotic maturation remain unclear. In the present study, to evaluate the roles of respective mTOR complexes in maternal meiosis and compare them with those in mitosis, we sought to elucidate the spatiotemporal immunolocalization of mTOR, the kinase-active Ser2448- and Ser2481-phosphorylated mTOR, and raptor and rictor during cumulus-cell mitosis and oocyte meiotic maturation in mice. mTOR principally accumulated around the chromosomes and on the spindle. Phosphorylated mTOR (Ser2448 and Ser2481) exhibited elevated fluorescence intensities in the cytoplasm and punctate localization adjacent to the chromosomes, on the spindle poles, and on the midbody during mitotic and meiotic maturation, suggesting functional homology of mTOR between the 2 cell-division systems, despite their mechanistically distinctive spindles. Raptor colocalized with mTOR during both types of cell division, indicating that mTORC1 is predominantly associated with these events. Mitotic rictor uniformly distributed through the cytoplasm, and meiotic rictor localized around the spindle poles of metaphase-I oocytes, suggesting functional divergence of mTORC2 between mitosis and female meiosis. Based on the general function of mTORC2 in the organization of the actin cytoskeleton, we propose that mTORC1 controls spindle function during mitosis and meiosis, while mTORC2 contributes to actin-dependent asymmetric division during meiotic maturation in mice. Mol. Reprod. Dev. ? 2013 Wiley Periodicals, Inc.
Expression regulated by
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Ovarian localization
Oocyte, Cumulus, Granulosa, Theca
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A putative mitotic checkpoint dependent on mTOR function controls cell proliferation and survival in ovarian granulosa cells. Yaba A et al. The conserved target of rapamycin (TOR) proteins are involved in sensing nutrient levels and/or stress and the resultant control of cell growth, size, and survival. The authors assess mammalian TOR (mTOR) kinase expression in the mouse ovary and also the expression of its cofactors, Raptor, Rictor, and LST8. In granulosa cells, mTOR demonstrates high cytoplasmic/perinuclear expression. The kinase-active serine 2448-phosphorylated form of mTOR (P-mTOR) is present at very high levels during the M-phase. P-mTOR was enriched on or near the mitotic spindle and also near the contractile ring during cytokinesis. Rapamycin inhibition of mTOR resulted in both reduced granulosa cell proliferation and reduced follicle growth in vitro, each in a dose-dependent fashion. Follicles cultured in rapamycin did not undergo atresia. mTOR inhibition results in a reduction in granulosa cell proliferation, supporting a model in which stress and nutritional cues may directly influence ovarian follicle growth.
Follicle stages
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Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: type: null mutation fertility: subfertile Comment: Rictor/mTORC2 in oocytes regulates folliculogenesis and its inactivation causes premature ovarian failure. Chen Z et al. (2015) Molecular basis of ovarian folliculogenesis and etiopathogenisis of pemature ovarian failure (POF), a common cause of infertility in women, are not fully understood. Mechanistic target of rapamycin complex 2 (mTORC2) s is emerging as a central regulator of cell metabolism, proliferation and survival. However, its role in folliculogenesis and POF has not been reported. Here, we showed that the signaling activity of mTORC2 is inhibited in a 4-vinylcyclohexene diepoxide (VCD)-induced POF mouse model. Notably, mice with oocyte-specific ablation of Rictor, a key component of mTORC2, demonstrated POF phenotypes, including massive follicular death, excessive loss of functional ovarian follicles, abnormal gonadal hormone secretion and consequently, secondary subfertility in conditional knockout (cKO) mice. Furthermore, reduced levels of S473-phosphorylated Akt and S253-phosphorylated Foxo3a and elevated proapoptotic proteins, Bad, Bax and cleaved-PARP, were observed in cKO mice, replicating the signaling alterations in 4-VCD-treated ovaries. These results indicate a critical role of the Rictor/mTORC2/Akt/Foxo3a pro-survival signaling axis in folliculogenesis. Interestingly, loss of maternal Rictor did not cause obvious developmental defects in embryos or placentas from cKO mice, suggesting that maternal Rictor is dispensable for pre-implantation embryonic development. Our results collectively indicate key roles of Rictor/mTORC2 in folliculogenesis, follicle survival and female fertility, and support the utility of oocyte-specific Rictor knockout mice as a novel model for POF.//////////////////