IndraLab
Statements
"Class I PI3K, a heterodimer consisting of a regulatory and a catalytic subunit, is a negative regulator of autophagy that is activated by the insulin receptor and the insulin receptor substrate proteins. Activated class I PI3K mainly uses PtdIns(4,5)P2 as substrate to yield PtdIns(3,4,5)P3 at the plasma membrane, which increases membrane recruitment of both PKB/Akt and its activator phosphoinositide- dependent protein kinase 1, leading to the activation of PKB/Akt, a downstream negative regulator of autophagy. Activated PKB/Akt further activates mTOR through inhibiting a downstream protein complex, the tuberous sclerosis complex 1/2, that represses the small G protein Rheb, causing inhibition of autophagy."
"Although the mechanism through which the TSC1-TSC2 complex represses mTOR signalling is incompletely defined, recent studies (Garami et al. 2003; Zhang et al. 2003) have suggested that, in part, TSC2 may act through the small GTPase ras homologue enriched in brain (Rheb) in regulating mTOR. Here, TSC2 is a GTPase-activating protein for Rheb that normally represses Rheb function (Garami et al. 2003; Zhang et al. 2003). How Rheb modulates mTOR-dependent signalling is unknown."
"Genetic support for a linear Akt1-mTOR-p70S6K pathway has recently come from reports demonstrating that the tuberous sclerosis complex 1 and 2 proteins (Tsc1 and Tsc2) can inhibit mTOR (Fig. 1). Akt1 phosphorylates Tsc2, thereby activating mTOR at least in part by disrupting the Tsc1-Tsc2 complex [54]."
"Genetic support for a linear Akt1-mTOR-p70S6K pathway has recently come from reports demonstrating that the tuberous sclerosis complex 1 and 2 proteins (Tsc1 and Tsc2) can inhibit mTOR (Fig. 1). Akt1 phosphorylates Tsc2, thereby activating mTOR at least in part by disrupting the Tsc1-Tsc2 complex [54]."
"Although the mechanism through which the TSC1-TSC2 complex represses mTOR signalling is incompletely defined, recent studies (Garami et al. 2003; Zhang et al. 2003) have suggested that, in part, TSC2 may act through the small GTPase ras homologue enriched in brain (Rheb) in regulating mTOR. Here, TSC2 is a GTPase-activating protein for Rheb that normally represses Rheb function (Garami et al. 2003; Zhang et al. 2003). How Rheb modulates mTOR-dependent signalling is unknown."
"Involvement of Rheb in the insulin TOR S6K signaling pathway was further investigated in mammalian cells. Transient transfection of Rheb1 or Rheb2 in HEK293 cells results in the increase of the phosphorylation of ribosomal S6 kinase (S6K) 25,30-33. Increase of the phosphorylation of S6 as well as 4E-BP1 was observed 30,31,33. In contrast, Rheb did not stimulate Akt phosphorylation 30,33]. The increase of S6K activity by the transient expression of Rheb was inhibited by the addition of rapamycin but not by wortmannin, an inhibitor of PI3K This led to the activation of S6K as detected by its phosphorylation. However, expression of dominant negative Rheb mutant, Rheb1D60K, blocked serum-inducted activation of S6K The overall picture of the involvement of Rheb in the insulin mTOR S6K signaling pathway is shown in Fig. 3. During serum activation of this signaling pathway, insulin or IGF1 is received by their respective receptors at the cell surface. This results in the activation of PI3K, which then phosphorylates Akt. The activated Akt phosphorylates Tsc2 and inhibits the ability of Tsc1 Tsc2 to negatively regulate mTOR. The inhibition of Tsc1 Tsc2 leads to the activation of Rheb, which then causes activation of mTOR. At least two downstream events, activation of p70S6K and phosphorylation of S6, as well as phosphorylation of 4E BP1 contribute to the increase in protein synthesis and progression of cell cycle49."
"Class I PI3K, a heterodimer consisting of a regulatory and a catalytic subunit, is a negative regulator of autophagy that is activated by the insulin receptor and the insulin receptor substrate proteins. Activated class I PI3K mainly uses PtdIns(4,5)P2 as substrate to yield PtdIns(3,4,5)P3 at the plasma membrane, which increases membrane recruitment of both PKB/Akt and its activator phosphoinositide- dependent protein kinase 1, leading to the activation of PKB/Akt, a downstream negative regulator of autophagy. Activated PKB/Akt further activates mTOR through inhibiting a downstream protein complex, the tuberous sclerosis complex 1/2, that represses the small G protein Rheb, causing inhibition of autophagy."