IndraLab
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"AMPK is known to be phosphorylated by the serine/threonine kinase LKB1 (Liver kinase B1) and to phosphorylate TSC2 (Tuberous Sclerosis Complex 2), a GAP (GTPase activating protein) domain containing protein, which inactivates the Rheb GTPase, a direct activator of MTORC1 (XREF_FIG)."
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"For instance, phosphorylation of TSC2 by ERK and RSK downstream of the growth factor responsive Ras-Raf-MEK pathway inhibits the TSC complex and leads to Rheb and mTORC1 activation, while phosphorylation of TSC2 by AMPK and GSK3 in response to energy stress (e.g. due to limiting levels of glucose) spurs the TSC complex to inhibit Rheb and mTORC1 [XREF_BIBR]."
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"The mammalian target of rapamycin (mTOR) signaling pathway senses both intracellular and extracellular signals and serves as a regulator of the fate of immune cell populations. [ xref ] The tuberous sclerosis (TSC) complex comprising TSC1 and TSC2 inhibits Rheb small GTPase directly, and Rheb is the upstream of the rapamycin‐sensitive complex 1 (mTORC1), thus to downregulate mTORC1 activity. [ xref ] Genetic loss of TSC1 increased proinflammatory response in macrophages while highly resist to IL4 induced M2 polarization. [ xref ] Activation of mTORC1 accelerates the synthesis of fatty acids and cholesterol though the transcriptional factor peroxisome proliferator activated receptor‐ γ (PPAR γ ), which promotes the metabolic reprograming in the anti‐inflammatory macrophages. [ xref ] While the activation of mTORC1 is relatively well understood at the level of nutrients, growth factors and signal transduction, the post‐transcriptional regulation of the component expression in the mTORC1 pathway remain less clear."
"Tsc2 functions as a gap to inhibit rheb activity. Tsc2 displays gap (gtpase-activating protein) activity specifically towards the small g protein rheb and inhibits its ability to stimulate the mtor signaling pathway. It has recently been shown that tsc2 has gtpase-activating protein (gap) activity towards the ras family small gtpase rheb (ras homolog enriched in brain), and tsc1/2 antagonizes the mtor signaling pathway via stimulation of gtp hydrolysis of rheb."
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"Functional assays in cells expressing Flag tagged WT-TSC2 or PxBS TSC2 mutants (RQ, RW, and RG) co-transfected with Flag-TSC1, myc-Rheb and either HA-S6K (XREF_FIG, left panel) or HA-4E-BP1 (XREF_FIG, right panel) showed that while WT-TSC2 suppressed Rheb activation of mTORC1 (evidenced by decreased phosphorylation of S6K1 and 4E-BP1 and [32 P]-radiolabeled-S6), all three pathogenic PxBS TSC2 mutants were deficient in mTORC1 repression (XREF_FIG)."
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"mTOR function can be decreased by three mechanisms : 1) TSC2 phosphorylation by AMPK deactivates Rheb GTPase and, consequently, inhibits TORC1; 2) inhibition of Raptor and RPTOR, a component of TORC1, results in TORC1 recruitment to 14-3-3 proteins, and 3) amino acid starvation can decrease mTOR activity through Rag GTPases."
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"Akt activates mTOR through (i) phosphorylation and inhibition of tuberous sclerosis complex 2 (TSC2), which inactivates the mTOR-activating GTP-binding protein Rheb, and/or (ii) phosphorylation of PRAS40 a member of mTORC1, one of the two functional complexes of mTOR, which includes mLST8/Gbl and the scaffold protein Raptor ( xref )."
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"This inhibition of mTORC1 activity is achieved either via the AMPK-dependent phosphorylation and activation of TSC2 and consequent inhibition of the GTPase Rheb or via inhibition of the GTPase Rag and consequent prevention of the lysosomal localization of mTORC1 triggered by amino acids."
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"AMPK can phosphorylate Raptor (regulatory associated protein of mTOR), an essential component of mTOR complex 1 (mTORC1), the activity of which blocks autophagy or can phosphorylate TSC2 (tuberous sclerosis complex 2) that directly inhibits Ras homolog enriched in brain (Rheb)-mediated mTORC1activation."
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"Like mTORC1, AMPK is also activated at the lysosome in response to low cellular energy levels (as is the case in Pompe muscle xref ) and promotes autophagy on two fronts - by TSC2 (the tuberous sclerosis complex)-mediated inhibition of RHEB (an activator of mTORC1) and by activating ULK1 at multiple sites (e.g Ser317 and Ser777) that are different from those of mTORC1 xref ."
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"Consistently, MTORC1 is dysregulated in many cancer types, xref and several compounds for pharmacological MTORC1 inhibition are investigated as cancer therapeutics. xref The MTORC1-specific allosteric inhibitor rapamycin and its analogs (rapalogs) are already approved for the treatment of several tumor entities. xref The more recently developed ATP-analog MTOR inhibitors, such as Torin1 13 and its derivatives, are currently tested in clinical studies. xref They target both MTOR complexes, and also inhibit MTORC1 functions which are insensitive to rapamycin. xref Amino acid- and growth factor- induced signaling pathways converge at the lysosomes to synergistically activate MTORC1. xref MTORC1 activation by amino acids requires RAG GTPase-mediated MTORC1 translocation to lysosomes. xref Conversely, loss of lysosomal MTORC1 association mediates MTORC1 inhibition upon amino acid withdrawal. xref At the lysosome, MTORC1 encounters the small GTPase Ras homolog enriched in brain (RHEB), xref which activates MTORC1 downstream of the INSR (insulin receptor)-phosphoinositide 3-kinase-AKT signaling axis. xref RHEB is inhibited by the heteromeric TSC1-TSC2 (tuberous sclerosis 1 and 2) complex, which acts as a GTPase-activating protein (GAP) on RHEB."
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"Both TORC1 and TORC2 complexes and their upstream regulators such as the TSC1–TSC2 (hamartin and tuberin, respectively) protein complex that represses TORC1 by affecting Rheb, a G-protein that acts as positive regulator of this complex [33], show great conservation within eukaryotes (Figure 1B)."