The mechanistic target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate organismal growth and homeostasis. The pathway regulates many major cellular processes and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration. Here, we review recent advances in our understanding of the mTOR pathway and its role in health, disease, and aging. We further discuss pharmacological approaches to treat human pathologies linked to mTOR deregulation.

mTOR Signaling in Growth Control and Disease

mTOR signaling in growth control and disease.

In certain aspects, the invention relates to methods for identifying compounds which modulate Akt activity mediated by the rictor-mTOR complex and methods for treating or preventing a disorder that is associated with aberrant Akt activity.

http://science.sciencemag.org/content/sci/307/5712/1098.full.pdf

Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex

The evolutionarily conserved checkpoint protein kinase, TOR (target of rapamycin), has emerged as a major effector of cell growth and proliferation via the regulation of protein synthesis. Work in the last decade clearly demonstrates that TOR controls protein synthesis through a stunning number of downstream targets. Some of the targets are phosphorylated directly by TOR, but many are phosphorylated indirectly. In this review, we summarize some recent developments in this fast-evolving field. We describe both the upstream components of the signaling pathway(s) that activates mammalian TOR (mTOR) and the downstream targets that affect protein synthesis. We also summarize the roles of mTOR in the control of cell growth and proliferation, as well as its relevance to cancer and synaptic plasticity.

/pdf/upstream-and-downstream-of-mtor-2v5cvgfhmb.pdf

Upstream and downstream of mTOR

LTP and LTD: an embarrassment of riches.

The complex of rapamycin with its intracellular receptor, FKBP12, interacts with RAFT1/FRAP/mTOR, the in vivo rapamycin-sensitive target and a member of the ataxia telangiectasia mutated (ATM)-related family of kinases that share homology with the catalytic domain of phosphatidylinositol 3-kinase The function of RAFT1 in the rapamycin-sensitive pathway and its connection to downstream components of the pathway, such as p70 S6 kinase and 4E-BP1, are poorly understood Here, we show that RAFT1 directly phosphorylates p70S6k, 4E-BP1, and 4E-BP2 and that serum stimulates RAFT1 kinase activity with kinetics similar to those of p70S6k and 4E-BP1 phosphorylation RAFT1 phosphorylates p70S6k on Thr-389, a residue whose phosphorylation is rapamycin-sensitive in vivo and necessary for S6 kinase activity RAFT1 phosphorylation of 4E-BP1 on Thr-36 and Thr-45 blocks its association with the cap-binding protein, eIF-4E, in vitro, and phosphorylation of Thr-45 seems to be the major regulator of the 4E-BP1–eIF-4E interaction in vivo RAFT1 phosphorylates p70S6k much more effectively than 4E-BP1, and the phosphorylation sites on the two proteins show little homology This raises the possibility that, in vivo, an unidentified kinase analogous to p70S6k is activated by RAFT1 phosphorylation and acts at the rapamycin-sensitive phosphorylation sites of 4E-BP1

https://www.pnas.org/content/pnas/95/4/1432.full.pdf

RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1

Cain, a novel physiologic protein inhibitor of calcineurin.

Immunophilins in the Nervous System

RAFT1 (rapamycin and FKBP12 target 1; also called FRAP or mTOR) is a member of the ATM (ataxia telangiectasia mutated)-related family of proteins and functions as the in vivo mediator of the effects of the immunosuppressant rapamycin and as an important regulator of messenger RNA translation. In mammalian cells RAFT1 interacted with gephyrin, a widely expressed protein necessary for the clustering of glycine receptors at the cell membrane of neurons. RAFT1 mutants that could not associate with gephyrin failed to signal to downstream molecules, including the p70 ribosomal S6 kinase and the eIF-4E binding protein, 4E-BP1. The interaction with gephyrin ascribes a function to the large amino-terminal region of an ATM-related protein and reveals a role in signal transduction for the clustering protein gephyrin.

https://science.sciencemag.org/content/sci/284/5417/1161.full.pdf

Patrick E. Burnett

Papers

RAFT1 phosphorylation of the translational regulators p70 S6 kinase and 4E-BP1

Cain, a novel physiologic protein inhibitor of calcineurin.

Immunophilins in the Nervous System

Interaction of RAFT1 with Gephyrin Required for Rapamycin-Sensitive Signaling

The Calcineurin-Dynamin 1 Complex as a Calcium Sensor for Synaptic Vesicle Endocytosis *