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

Abstract

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.

A model of our current understanding of the relationship between Akt, the TSC1-TSC2 complex and the mTOR complexes

PI3K is activated by growth factors through direct interaction with receptors or through interaction with scaffolding adaptors, such as the IRS proteins. These interactions recruit PI3K to its substrate phosphatidylinositol-4,5-bisphosphate (PIP2) allowing generation of the lipid second messenger phosphatidylinositol-3,4,5-trisphosphate (PIP3). Akt and PDK1 are recruited to the plasma membrane through association with PIP3. This allows Akt to be activated through phosphorylation on Thr-308 by PDK1 and Ser-473 by mTORC2. Once active, Akt phosphorylates many downstream targets, including multiple sites on TSC2, which forms a functional complex with TSC1. Phosphorylation of TSC2 impairs the ability of the TSC1-TSC2 complex to act as a GAP toward the small GTPase Rheb, allowing Rheb-GTP to accumulate. Through poorly defined mechanism, Rheb-GTP potently activates mTORC1, which phosphorylates and inhibits 4E-BP1 and activates S6K1 and S6K2. A negative feedback loop exists in which mTORC1 and S6K1 directly phosphorylate IRS-1 and block insulin or IGF-1 signaling to PI3K. Growth factors also increase mTORC2 activity, albeit through unknown signaling events. Through a mechanism distinct from its regulation of Rheb and mTORC1, the TSC1-TSC2 complex can bind to mTORC2 and is required for mTORC2 activation. In addition, the TSC1-TSC2 complex appears to be involved in the phosphorylation of PKCα by mTORC2. Unlike Akt, PDK1 phosphorylates both S6K1/2 and PKCα in a manner independent of PIP3 binding. Finally, the drug rapamycin strongly and acutely inhibits mTORC1, while it only affects mTORC2 assembly and activity after prolonged exposure.