The target of rapamycin (TOR) proteins

Abstract

Rapamycin potently inhibits downstream signaling from the target of rapamycin (TOR) proteins. These evolutionarily conserved protein kinases coordinate the balance between protein synthesis and protein degradation in response to nutrient quality and quantity. The TOR proteins regulate (i) the initiation and elongation phases of translation, (ii) ribosome biosynthesis, (iii) amino acid import, (iv) the transcription of numerous enzymes involved in multiple metabolic pathways, and (v) autophagy. Intriguingly, recent studies have also suggested that TOR signaling plays a critical role in brain development, learning, and memory formation.

Figures

Figure 1

The Tor proteins regulate the balance between protein synthesis and protein degradation. TOR signaling is active in the presence of sufficient nutrients to fuel protein synthesis. The TOR signal allows for the translation of mRNAs coding for components of the translation machinery, ribosome biosynthesis, and the stabilization of high affinity amino acid permeases. At the same time, TOR signaling destabilizes general amino acid permeases, inhibits autophagy, and represses the transcription of a subset of genes required for amino acid biosynthesis.

Figure 2

Signaling to eukaryotic translation initiation and elongation factors. mTOR signaling, in combination with the PI3K pathway, activates the translation of rapamycin-sensitive mRNAs. In the presence of sufficient nutrients to fuel protein synthesis, mTOR and PI3K signaling activate the S6Ks, and one or more unknown kinases, to effect phosphorylation of the ribosomal S6 protein, eIF4B, eIF4GI, and the 4E-BPs. In response to agents that raise intracellular Ca2+ (such as glutamate or NMDA), a specific Ca2+/CaM-dependent kinase effects the phosphorylation of eEF2 to inhibit elongation. mTOR signaling has been reported to inhibit eEF2 phosphorylation (possibly via inhibition of the eEF2 kinase), and thus, to increase elongation rates. Phosphatases have been implicated in the dephosphorylation of several translation effectors, but are not depicted in this figure.

Figure 3

The initiation and elongation phases of translation in eukaryotes. In starved or stressed cells, the cap binding protein eIF4E is sequestered by hypophosphorylated 4E-BPs. In growing or stimulated cells, the 4E-BPs are hyperphosphorylated to release eIF4E, such that it can interact with the scaffolding protein, eIF4G. In conjunction with the RNA helicase eIF4A and the cofactor eIF4B, 5′ secondary structure is melted, and a small ribosomal subunit is recruited to a single-stranded, cap-proximal region of an mRNA via an interaction between eIF4G and the ribosome-associated factor eIF3. The small ribosomal subunit, along with a ternary complex composed of eIF2, GTP, and Met-tRNAi, then scans the mRNA in a 5′ to 3′ direction until an AUG start codon in the proper sequence context is encountered. At this point, initiation factors are released, and the large ribosomal subunit is recruited. The elongation factors catalyze aminoacyl-tRNA binding to ribosomes, and the translocation of the mRNA from the ribosomal A site to the P site.