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. Rapamycin Inhibits Long-Term FacilitationS ynaptic plasticity, the capacity of neurons to modulate the strength of synaptic connections, is believed to be critical for learning and memory formation. Long-term synaptic plasticity (necessary for the formation of long-term memory) requires alterations in gene expression and the establishment of new synaptic connections (1-3). These findings presented an interesting dilemma: That is, how can changes in gene expression in the cell body alter the strength of individual synaptic connections? Recent data suggest that stimulated synapses are ''tagged'' to capture mRNAs produced in the soma and exported throughout the cell (4). Synaptic tagging thus results in localization of mRNAs only to those synapses marked by previous activity. This model also presupposes that long-term plasticity depends on local translation of the localized mRNAs. Indeed, ribosomes, tRNAs, translation initiation factors, and translation elongation factors are found in dendrites (5, 6), and protein synthesis has been demonstrated to occur in isolated synaptic bodies (7,8). Functional studies have demonstrated that protein synthesis is required for potentiation of synaptic transmission elicited by neurotrophic factors in hippocampal slices (9), and for the establishment of long-term facilitation in Aplysia neurons (10). Kandel and coworkers implicated a specific intracellular signaling pathway in this process by demonstrating that serotoninstimulated synaptic protein synthesis can be blocked with rapa-

Molecular Mechanisms of Insulin Resistance: Serine Phosphorylation of Insulin Receptor Substrate-1 and Increased Expression of p85α

“…A cellular nutrient sensor, mTOR, has been identified as a critical element integrating cellular metabolism with growth factor signaling (42)(43)(44)(45). In response to insulin and amino acids, mTOR, which is a serine/threonine kinase, phosphorylates and modulates activities of p70 S6 kinase (S6K1 kinase) and an inhibitor of translational initiation, eIF-4E binding protein (46 -48).…”

Regulation of cyclin D1 expression by mTORC1 signaling requires eukaryotic initiation factor 4E-binding protein 1

“…The best-described targets for mTOR are the ribosomal protein S6 kinases (S6Ks) and eukaryotic initiation factor 4E-binding protein 1 (4E-BP1, Raught et al, 2001). Hypophosphorylated 4E-BP1 binds eIF4E and so inhibits the formation of translation initiation complexes (eIF4F).…”

Translational Control via the Mammalian Target of Rapamycin Pathway Is Critical for the Formation and Stability of Long-Term Fear Memory in Amygdala Neurons

“…The signaling pathway controlled by the mammalian target of rapamycin (mTOR) kinase regulates protein translation by controlling the phosphorylation state of the eIF4E-binding protein 1 (4E-BP1) and p70s6 kinase (p70s6K) (for review, see Raught et al, 2001). Rapamycin (RAP) is an inhibitor of the mTOR pathway, and work in various preparations has pointed to this pathway as being critical for different types of synaptic plasticity (Casadio et al, 1999;Tang et al, 2002;Cammalleri et al, 2003).…”