A complex interplay between Akt, TSC2 and the two mTOR complex

Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
Biochemical Society Transactions (Impact Factor: 3.19). 03/2009; 37(Pt 1):217-22. DOI: 10.1042/BST0370217
Source: PubMed


Akt/PKB (protein kinase B) both regulates and is regulated by the TSC (tuberous sclerosis complex) 1-TSC2 complex. Downstream of PI3K (phosphoinositide 3-kinase), Akt phosphorylates TSC2 directly on multiple sites. Although the molecular mechanism is not well understood, these phosphorylation events relieve the inhibitory effects of the TSC1-TSC2 complex on Rheb and mTORC1 [mTOR (mammalian target of rapamycin) complex] 1, thereby activating mTORC1 in response to growth factors. Through negative-feedback mechanisms, mTORC1 activity inhibits growth factor stimulation of PI3K. This is particularly evident in cells and tumours lacking the TSC1-TSC2 complex, where Akt signalling is severely attenuated due, at least in part, to constitutive activation of mTORC1. An additional level of complexity in the relationship between Akt and the TSC1-TSC2 complex has recently been uncovered. The growth-factor-stimulated kinase activity of mTORC2 [also known as the mTOR-rictor (rapamycin-insensitive companion of mTOR) complex], which normally enhances Akt signalling by phosphorylating its hydrophobic motif (Ser(473)), was found to be defective in cells lacking the TSC1-TSC2 complex. This effect on mTORC2 can be separated from the inhibitory effects of the TSC1-TSC2 complex on Rheb and mTORC1. The present review discusses our current understanding of the increasingly complex functional interactions between Akt, the TSC1-TSC2 complex and mTOR, which are fundamentally important players in a large variety of human diseases.

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Available from: Jingxiang Huang, Mar 12, 2014
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    • "" mTORC2 phosphorylates the serine/threonine protein kinase Akt/PKB at a serine residue S473. Phosphorylation of the serine stimulates Akt phosphorylation at a threonine T308 residue by PDK1 and leads to full Akt activation [13] [16] [17]; mTORC2 appears to be regulated by insulin, growth factors, serum, and nutrient levels [6] [7]. Originally , mTORC2 was identified as a rapamycin-insensitive entity, as acute exposure to rapamycin did not affect mTORC2 activity or Akt phosphorylation. "
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    ABSTRACT: Rapamycin, an inhibitor of mTOR activity, is a potent inducer of erythroid differentiation and fetal hemoglobin production in β-thalassemic patients. Mithramycin (MTH) was studied to see if this inducer of K562 differentiation also operates through inhibition of mTOR. We can conclude from the study that the mTOR pathway is among the major transcript classes affected by mithramycin-treatment in K562 cells and a sharp decrease of raptor protein production and p70S6 kinase is detectable in mithramycin treated K562 cells. The promoter sequence of the raptor gene contains several Sp1 binding sites which may explain its mechanism of action. We hypothesize that the G+C-selective DNA-binding drug mithramycin is able to interact with these sequences and to inhibit the binding of Sp1 to the raptor promoter due to the following results: (a) MTH strongly inhibits the interactions between Sp1 and Sp1-binding sites of the raptor promoter (studied by electrophoretic mobility shift assays, EMSA); (b) MTH strongly reduces the recruitment of Sp1 transcription factor to the raptor promoter in intact K562 cells (studied by chromatin immunoprecipitation experiments, ChIP); (c) Sp1 decoy oligonucleotides are able to specifically inhibit raptor mRNA accumulation in K562 cells. In conclusion, raptor gene expression is involved in mithramycin-mediated induction of erythroid differentiation of K562 cells and one of its mechanism of action is the inhibition of Sp1 binding to the raptor promoter. Copyright © 2014. Published by Elsevier Ltd.
    Pharmacological Research 12/2014; 91. DOI:10.1016/j.phrs.2014.11.005 · 4.41 Impact Factor
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    • "Activated Akt in turn phosphorylates and inhibits the tuberous sclerosis complex 2 (TSC2), thus preventing the formation of the inhibitory TSC1/TSC2 heterodimer. This inhibition allows the small GTPase Rheb to activate directly mTORC1 (Long et al., 2005a,b; Huang and Manning, 2009) and to inhibit autophagy. Another signaling pathway controlling mTOR is the adenosine monophosphate-activated protein kinase (AMPK) pathway activated under energy-low conditions (Alers et al., 2012). "
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    ABSTRACT: Muscular dystrophies are a group of genetic and heterogeneous neuromuscular disorders characterized by the primary wasting of skeletal muscle. In Duchenne muscular dystrophy (DMD), the most severe form of these diseases, the mutations in the dystrophin gene lead to muscle weakness and wasting, exhaustion of muscular regenerative capacity, and chronic local inflammation leading to substitution of myofibers by connective and adipose tissue. DMD patients suffer from continuous and progressive skeletal muscle damage followed by complete paralysis and death, usually by respiratory and/or cardiac failure. No cure is yet available, but several therapeutic approaches aiming at reversing the ongoing degeneration have been investigated in preclinical and clinical settings. Autophagy is an important proteolytic system of the cell and has a crucial role in the removal of proteins, aggregates, and organelles. Autophagy is constantly active in skeletal muscle and its role in tissue homeostasis is complex: at high levels, it can be detrimental and contribute to muscle wasting; at low levels, it can cause weakness and muscle degeneration, due to the unchecked accumulation of damaged proteins and organelles. The causal relationship between DMD pathogenesis and dysfunctional autophagy has been recently investigated. At molecular level, the Akt axis is one of the key dysregulated pathways, although the molecular events are not completely understood. The aim of this review is to describe and discuss the clinical relevance of the recent advances dissecting autophagy and its signaling pathway in DMD. The picture might pave the way for the development of interventions that are able to boost muscle growth and/or prevent muscle wasting.
    Frontiers in Aging Neuroscience 07/2014; 6:188. DOI:10.3389/fnagi.2014.00188 · 4.00 Impact Factor
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    • "Inhibition of mTOR has been shown to inhibit proteasomal degradation of IRS-1 (38–40) enhancing signaling through the PI-3 kinase/Akt pathway. Because Akt is known to antagonize apoptotic processes and has a complex relationship with mTOR signaling as it is both regulated by TORC2 and acts to regulate TORC1 activity (41), differences in Akt activity could contribute to the enhanced survival of cells treated with rapamycin. The increase in Akt phosphorylation is interesting when considered in the light of the reduced growth rate of cells maintained in the presence of rapamycin (29). "
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    ABSTRACT: The regulation of mitochondrial mass and DNA content involves a complex interaction between mitochondrial DNA replication machinery, functional components of the electron transport chain, selective clearance of mitochondria, and nuclear gene expression. In order to gain insight into cellular responses to mitochondrial stress, we treated human diploid fibroblasts with ethidium bromide at concentrations that induced loss of mitochondrial DNA over a period of 7 days. The decrease in mitochondrial DNA was accompanied by a reduction in steady state levels of the mitochondrial DNA binding protein, TFAM, a reduction in several electron transport chain protein levels, increased mitochondrial and total cellular ROS, and activation of p38 MAPK. However, there was an increase in mitochondrial mass and voltage dependent anion channel levels. In addition, mechanistic target of rapamycin (mTOR) activity, as judged by p70S6K targets, was decreased while steady state levels of p62/SQSTM1 and Parkin were increased. Treatment of cells with rapamycin created a situation in which cells were better able to adapt to the mitochondrial dysfunction, resulting in decreased ROS and increased cell viability but did not prevent the reduction in mitochondrial DNA. These effects may be due to a more efficient flux through the electron transport chain, increased autophagy, or enhanced AKT signaling, coupled with a reduced growth rate. Together, the results suggest that mTOR activity is affected by mitochondrial stress, which may be part of the retrograde signal system required for normal mitochondrial homeostasis.
    Frontiers in Endocrinology 07/2014; 5:122. DOI:10.3389/fendo.2014.00122
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