mTOR signaling: at the crossroads of plasticity, memory and disease

Abstract

Mammalian target of rapamycin (mTOR) is a protein kinase involved in translation control and long-lasting synaptic plasticity. mTOR functions as the central component of two multi-protein signaling complexes, mTORC1 and mTORC2, which can be distinguished from each other based on their unique compositions and substrates. Although the majority of evidence linking mTOR function to synaptic plasticity comes from studies utilizing rapamycin, studies in genetically modified mice also suggest that mTOR couples receptors to the translation machinery for establishing long-lasting synaptic changes that are the basis for higher order brain function, including long-term memory. Finally, perturbation of the mTOR signaling cascade appears to be a common pathophysiological feature of human neurological disorders, including mental retardation syndromes and autism spectrum disorders.

Figure 1. mTOR structure

Mammalian target of rapamycin (mTOR) is large multi-domain protein. The N-terminal portion of mTOR contains more than 20 Huntingtin, Elongation Factor 3, A subunit of PP2A, TOR1 (HEAT) repeats. These HEAT repeats form a large helical secondary structure that provides protein interaction activity (dashed lines) with mTOR complex members such as Regulatory-associated protein with TOR (Raptor) and Rapamycin-insensitive companion of TOR (Rictor). The C-terminal portion of mTOR contains several important domains. The first is the FRAP (FKBP12-rapamycin-associated protein)/TOR), ATM, (ataxia-telangiectasia), TRRAP (transactivation/transformation domain-associated protein) (FAT) domain. The FAT domain is a conserved domain among PIKK family members. A second FAT domain (FATC) is located at the distal C-terminal end of mTOR. Both FAT domains are necessary for mTOR catalytic function. Adjacent to the FAT domain is the FKBP12-rapamycin binding (FRB) domain. This domain is bound by the FKBP12-rapamycin complex and is a site of interaction between mTOR and FKBP family members bound to rapamycin. The FRB also is involved in the interaction between mTOR and other mTORC members including (Raptor) and Ras-homolog enriched in the brain (Rheb). The catalytic or kinase (KIN) domain is flanked by the FAT domains and encodes the serine/threonine kinase activity of mTOR. Within the KIN domain is a region that is sometimes referred to as the negative regulatory domain (NRD), which contains serine and threonine residues that are phosphorylated and are involved in the regulation of mTOR activity. Threonine 2246 is targeted by AMPK and S6K, serine 2448 is a target of Akt and S6K, and serine 2481 is autocatalytic target of mTOR.

Figure 2. Signaling upstream and downstream of mTORC1 and mTORC2

Neuronal receptors and channels (NMDAR, Trk-B, mGluR D1R, and D2R) activate downstream signaling pathways leading to mTORC1 activation. The upstream signaling regulating mTORC2 activity in neurons is currently unknown. mTORC1 activity regulates several downstream effectors of translation (S6K, 4E-BP, eEF2K) both somatically and dendritically in neurons. mTORC2 may modulate the activity of mTORC1 either directly (S2448) or indirectly (Akt, cPKC, S6K). mTORC1 substrates (S6K) can phosphorylate Rictor enabling crosstalk between the two TORC complexes. mTORCs regulate several critical neuronal metabolisms including translation, cytoskeletal structure, protein stability and signal transduction. Abbreviations used: Akt/protein kinase B (Akt/PKB), brain-derived neurotrophic factor (BDNF), conventional protein kinase C (cPKC), Dopamine receptor type 1 (D1R), dopamine receptor type 2, (D2R) extracellular signal-regulated protein kinase (ERK), eukaryotic initiation factor 4E-binding protein (4E-BP), eukaryotic elongation factor 2 Kinase (eEF2 K), FK506-binding protein 12 (FKBP12), G_q-protein (Gq), insulin response element (IRS), mammalian lethal with sec 13 (mLST8), metabotropic glutamate receptor (mGluR), mammalian target of rapamycin (mTOR), N-methyl-D-aspartate receptor (NMDAR), phosphoinositide-3 kinase (PI3K), mTOR complex 1 (mTORC1), mTOR complex 2 (mTORC2), phosphoinositide-dependent kinase 1 (PDK1), proline-rich Akt/PKB substrate 40 kD (PRAS40), protein observed with rictor (Protor), Regulatory-associated protein with TOR (Raptor), Ras homolog enriched in brain (Rheb), Rapamycin- insensitive companion of mTOR (Rictor), p90 ribosomal S6K kinase 2 (Rsk2), SAPK (Sin1), p70 S6 Kinase (S6K), serum- and glucorticoid inducible kinase (SGK), tyrosine receptor kinase-B (TrkB) tuberous sclerosis complex 1 and 2 (TSC1/2). T=threonine, S=serine (number denotes residue phosphorylated), Red (P) denotes inhibitory regulation; Green (P) denotes stimulatory regulation.