A comprehensive map of the mTOR signaling network

Abstract

The mammalian target of rapamycin (mTOR) is a central regulator of cell growth and proliferation. mTOR signaling is frequently dysregulated in oncogenic cells, and thus an attractive target for anticancer therapy. Using CellDesigner, a modeling support software for graphical notation, we present herein a comprehensive map of the mTOR signaling network, which includes 964 species connected by 777 reactions. The map complies with both the systems biology markup language (SBML) and graphical notation (SBGN) for computational analysis and graphical representation, respectively. As captured in the mTOR map, we review and discuss our current understanding of the mTOR signaling network and highlight the impact of mTOR feedback and crosstalk regulations on drug-based cancer therapy. This map is available on the Payao platform, a Web 2.0 based community-wide interactive process for creating more accurate and information-rich databases. Thus, this comprehensive map of the mTOR network will serve as a tool to facilitate systems-level study of up-to-date mTOR network components and signaling events toward the discovery of novel regulatory processes and therapeutic strategies for cancer.

MicroRNA-100 Resensitizes Resistant Chondrosarcoma Cells to Cisplatin through Direct Targeting of mTOR

“…mTOR is frequently activated in multiple carcinoma and can be a promising therapeutic target in the treatments of clinical cancer patients. mTOR phosphorylates p70 S6 kinase (p70S6K) and the 4E-BP1 translational repressor, leading to translation of proteins required for cell proliferation (Caron et al, 2010;Laplante et al, 2012). It has been reported that AKT-mTOR signaling is frequently activated in epithelial ovarian cancer (Caron et al, 2010;Steelman et al, 2011).…”

“…mTOR phosphorylates p70 S6 kinase (p70S6K) and the 4E-BP1 translational repressor, leading to translation of proteins required for cell proliferation (Caron et al, 2010;Laplante et al, 2012). It has been reported that AKT-mTOR signaling is frequently activated in epithelial ovarian cancer (Caron et al, 2010;Steelman et al, 2011). Moreover, mTOR inhibition by BEZ235 has been reported be efficacious for the inhibition of chondrosarcoma cells growth in vitro (Zhang et al, 2013).…”

Systems‐based understanding of pharmacological responses with combinations of multidisciplinary methodologies

“…The cellular events occurring after drug exposure can be described by examining perturbations in the behavior of molecular networks within cells when drugs bind to their pharmacological/toxicological target(s). In vivo pharmacological/toxicological effects can be described by extrapolating drug responses from the cellular level to the tissue/organ and whole body levels One example is the map of mammalian target of rapamycin (mTOR)-related signal transduction pathways, which are regulated by many factors including the nutritional status of the cell and by stimulation by growth factors, Wnt ligands and TNF-α ( Figure 3a) [13]. The mTOR signal transduction pathway comprises approximately one thousand molecular entities.…”

“…Caron et al analysed the mTOR signal transduction pathway and showed that the system contains a feedback loop that links the downstream molecule in the main signal transduction pathway, S6K1, to the upstream AKT pathway (Figure 3b) [13]. According to this feedback loop, cells stimulated by Wnt ligands and growth factors, such as insulin-like growth factor (IGF) and fibroblast growth factor (FGF), activate S6K1, which in turn stimulates cell growth via mTOR complex 1 (mTORC1).…”

“…In addition, numerous somatic mutations have been reported in genes, which are associated with the development of cancer [12]. However, irrespective of such efforts, we still do not fully understand the mechanisms for the development of diseases, since multiple factors are often responsible for the disease development [13][14][15].…”