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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    • "The transient and slight decrease in Akt phosphorylation at S473 suggests that mTORC2 signaling is also decreased following MES. Although, the role of mTORC2 pathway in the development of seizure has been less studied, it is interesting to note the loss of function mutations or deletions of the TSC1 or TSC2 genes leading to spontaneous seizure and mTORC1 hyperactivation are associated with decreased mTORC2 signaling (Huang and Manning, 2009; Carson et al., 2013). Knowing its critical role in the control of actin polymerization , it is likely that inactivation of mTORC2 signaling contribute to structural remodeling of dendritic spines observed after seizures (Isokawa, 1998; Jiang et al., 1998; Zeng et al., 2007b). "
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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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    • "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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