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.

Figure 1

Graphical notations adopted by CellDesigner to illustrate the mTOR signaling network. (A) Process diagrams, explicitly displaying different phosphorylated forms of the TSC1–TSC2 complex, as well as the processes of phosphorylation on different serine and threonine residues by AKT, ERK1/2, RSK1/2, CDK1, AMPK, GSK3 and IKKβ. The active state of the molecule is indicated by a dashed line surrounding the molecule. Phosphorylation state of the component is represented with target residues and positions. For individual proteins and reactions, specific notes such as PubMed ID (PMID) were added, enabling a direct link to the relevant references. (B) Activity flow diagrams depicting the activation and inhibition of the TSC1–TSC2 complex by the enzymes illustrated in A. In this diagram language, the biochemical details are omitted.

Figure 2

A comprehensive map of the mTOR signaling network. This map was created with CellDesigner version 4.0.1. A total number of 777 reactions and 964 species were included. The SBML and PDF files of the mTOR map are available from the Supplementary information. The map can be best viewed in the PDF format (see Supplementary Figure S3). All of the species, proteins, reactions and cellular compartments included in the map are listed in the SBML file when opened by CellDesigner (http://celldesigner.org/). All of the unique proteins were listed in Supplementary Table S1. A cartoon view of the map (bottom right) depicting different functional modules was drawn to facilitate the exploration of the map. Symbols adopted to build the map are illustrated in the legend. This image is also available as high resolution PDF.

Figure 3

Upstream regulators of mTORC1 signaling. Species, proteins, reactions and cellular compartments involved in mTORC1 signaling were extracted from the comprehensive mTOR map and illustrated using the process diagram language. Green and red reactions indicate activation and inhibition of mTORC1, respectively. Size and color of each component are configurable. Symbols are similar to those used in the legend of the Figure 2. The SBML and PDF files (see Supplementary Figure S4) of mTORC1 signaling are available from the Supplementary information.

Figure 4

Activity flow of the mTOR signaling network. Central components and reactions were extracted from the comprehensive mTOR map and illustrated using the activity flow diagram language. This reduced map focuses on the flow of activation and inhibition and on the architecture of mTORC1 signaling. Components and signaling events related to mTORC1 consist of a possible bow-tie network (pale blue area). In this network architecture, input signals converge to TSC1–TSC2/Rheb/mTORC1, which forms the bow-tie core of the network. Activities of the core components have important roles in controlling diverse downstream responses. Positive and negative feedback loops in the network are represented by the bold lines. Green and red lines indicate activation and inhibition of mTORC1/2, respectively. The inhibition of mTORC1 by rapamycin, the inhibition mTORC1/2 by the ATP-competitive inhibitor Torin1, and the inhibition of MEK by CI-1040 are represented by the bold blue lines. Symbols are similar to those used in the legend of Figures 1 and 2. The SBML and PDF files (see Supplementary Figure S5) of the reduced mTOR map are available from the Supplementary information.