IndraLab

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STK11 inhibits MTOR. 92 / 97
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"This suggested that LKB1 inhibits Yap independently of mTOR."
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"Generally , metformin inhibits mammalian Target of Rapamycin ( mTOR ) activity by activating ATM ( ataxia telangiectasia mutated ) , Liver Kinase B1 ( LKB1 ) , and then AMPK , which ultimately prevents protein synthesis and cell growth [ 6 ] ."
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"Additionally, LKB1 inhibited Yap independently of either AMPK or mTOR activation."
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"69 Loss of LKB1 leads to activation of the mTOR and IGF-1R pathways."
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"Moreover, the activation of LKB1 and AMPK stimulates autophagy through phosphorylation of ULK1 and inhibits the mTOR pathway."
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"Of interest, HeLa cells are defective in the tumor suppressor protein LKB1, also known as STK11, which inhibits mTOR by a pathway impinging on TSC2 stimulation."
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"While the inhibition of mTOR activity as well as activation by the tumor suppressor LKB1 serve as a basis for AMPK 's anti-tumor effects, induction of potentially pro survival pathways like autophagy and glucose uptake have been proposed to challenge the molecule 's anti-cancer role [XREF_BIBR]."
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"The intestinal polyps in Peutz-Jeghers syndrome have up-regulated mTORC1 signaling, supporting the idea that STK11 loss results in mTOR activation (7)."
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"Liver kinase B1 ( LKB1 , tumour suppressor ) , an upstream kinase of AMP-activated protein kinase ( AMPK ) induces AMPK phosphorylation of tuberous sclerosis complex 2 ( TSC2 ) to suppress Ras homolog enriched in brain ( Rheb ) and inhibit mTOR ."
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"The LKB1 and AMPK pathway on the other hand, inhibits mTOR and activates NF-kappaB and Notch1."
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"It is likely that inability of LKB1 to effectively downregulate mTOR may be related to its failure to block tumorigenesis."
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"During starvation, Lkb1, an upstream kinase of AMPK, represses mTOR, which induces a reversible glycolytic and epigenetically H4K16Ac negative, diapause like state."
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"LKB1 acts through AMPK to inhibit mTOR, which regulates cell growth."
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"Metformin acts as an anti-tumor medication through stimulation of AMP-activated protein kinase (AMPK) and its regulator liver kinase B1 (LKB1), which inhibits the mammalian target of rapamycin (mTOR) and disrupts the life cycle of cancer cells."
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"STK11 negatively regulates the mTOR pathway by activation of AMPK [XREF_BIBR]."
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"In NSCLC cells in vitro, LKB1 and AMPK signaling was shown to negatively regulate mTOR activity and contribute to cell growth inhibition in response to 2-deoxyglucose (2-DG), which mimics energy stress."
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"LKB1 and AMPK dependent inhibition of the mTOR pathway acts as a tumor suppressor in transformed cells, contributing to cell growth inhibition and repression of oncogenic mRNA translation in response to energy stress [XREF_BIBR, XREF_BIBR]."
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"Additionally, HeLa cells are defective in the tumor suppressor LKB1, which inhibits mTOR via TSC2 stimulation."
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"Notably, we observed over-expression of AKT3 (an mTOR activator) and reduced expression of TSC2 (consistent with single copy loss of the gene) and STK11 which both inhibit mTOR activity."
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"Although mTOR is a known regulator of the cell size XREF_BIBR and Lkb1 can suppress mTOR via AMPK phosphorylation XREF_BIBR we did not find evidence of mTOR machinery misregulation in our model (XREF_FIG) suggesting relatively intact energy sensing mechanisms."
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"In response to energy stress, Lkb1, a kinase known to activate several AMP activated protein kinases (AMPK), inhibits the canonical mTOR pathway and impedes protein translation and cell growth."
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"In mouse endometrial and bladder cancers, loss of PTEN and LKB1 leads to activation of the AKT and mTOR pathway and results in tumors sensitivity to PI3K and mTOR inhibition."
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"Stromal Liver Kinase B1 [STK11] Signaling Loss Induces Oviductal Adenomas and Endometrial Cancer by Activating Mammalian Target of Rapamycin Complex 1."
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"Melanocytic nevi, a benign proliferation of melanocytes, which can give birth to malignant melanoma, show in many cases elevated PLD2 expression as well as activation of Akt, whereas LKB1 expression is still high in most cases, suppressing aberrant mTOR activation, which occurred only in 25% of the analysed specimen (XREF_FIG)."
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"By directly controlling the activation of these kinases , LKB1 inhibits mammalian target of rapamycin ( mTOR ) , a tumor-promoting kinase , and activates tuberous sclerosis 2 ( TSC2 ) and p53 , both of which are tumor suppressors 16 , 18 , 19 , 20 , 21 ."
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"This was a groundbreaking study because it provided in vivo evidence that the inactivation of LKB1 not only disrupts the regulation of mTOR signaling but also promotes cancer metastasis."
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"STK11 encodes serine/threonine protein kinase 11, also known as Lkb1, that activates AMPK, and negatively regulates the mTOR pathway in response to cellular energy levels."
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"While PTEN loss increases PIK3CA activity, LKB1 loss-of-function promotes mTOR signaling."
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"It was proposed that this inhibition of LKB1, which dampened AMPK signaling, thus potentiated mTOR activity and ultimately enhanced cell growth and proliferation."
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"Mechanistically, APE up-regulated the expression of SIRT1, activated LKB1 and AMPK pathway and inhibited mTOR signaling."
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"It had previously been suggested that loss of Lkb1 activity in Pkd1 mutant kidney epithelia promoted activation of the mTOR pathway and a switch in cellular metabolism towards glycolysis, a phenomenon referred to as the Warburg effect 23."
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"The tumor suppressor liver kinase B1 (LKB1) and AMPK control cell growth in response to environmental nutrient changes and downregulate the mTOR pathway [XREF_BIBR, XREF_BIBR]."
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"While these additional effects are intriguing, LKB1 dependent suppression of mTOR signaling remains the key candidate mechanism of antitumor action of metformin."
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"In addition, here we showed that loss of LKB1 could induce constitutive mTOR activation, even in the absence of detection of p-TSC2 (Thr 1462), and in vitro gain of LKB1 in OS cell lines shows a tumourigenic function."
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"In addition to PTEN, the LKB1 tumor suppressor pathway also negatively regulates mTOR signaling."
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"STK11 (LKB1) inhibited mTOR signaling."
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"Since the PI3K and Akt and MAPK and ERK signaling pathways, which positively regulate the mTOR axis, are often activated in many types of cancer, and LKB1, which suppresses mTOR signaling, is frequently mutated in certain types of cancers, mTOR signaling is consequently hyper-activated in many types of cancers."
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"Lkb1 and Pten Synergise to Suppress mTOR Mediated Tumorigenesis and Epithelial-Mesenchymal Transition in the Mouse Bladder."
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"In particular, GNA11 can act as an oncoprotein by activating mTOR signaling, whereas STK11 inhibits mTOR activity downstream of PTEN."
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"PTEN inhibits PI3K signaling in the absence of growth factors, and STK11 (LKB1) inhibits MTOR activity when ATP is low [XREF_BIBR]."
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"Ectopic expression of LKB1 with stable transduction system or inducible expression construct in endogenous LKB1 deficient cells improved the activation of AMPK, promoted the inhibition of mTOR, and prompted the sensitivity of cells to metformin."
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"MTOR is activated by HR HPV oncogene, XREF_BIBR - XREF_BIBR but inactivated by LKB1."
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"An additional link between Reelin and mTor signaling is suggested by the reciprocal regulation of Golgi morphology by Reelin-Dab1 and Lkb1 signaling, which also inhibits mTor by activating Tsc2."
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"However, most frequently, RSV is found to inhibit the activity of the mTOR pathway proteins, and to activate AMPK and LKB1, which can suppress mTOR signalling."
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"Conclusion SIRT4 could exert its tumor suppressive function in HCC by inhibiting glutamine metabolism and thereby increasing the ADP and AMP levels to phosphorylate AMPKalpha via LKB1, which blocks mTOR signaling pathway."
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"Since LKB1 is known to downregulate mTOR signaling by activating the AMPK signaling pathway 7, we further investigated the effect of p53 on LKB1 regulated AMPK and mTOR pathway."
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"Deletion of Lkb1 in adipose tissues has been reported to activate the mTOR pathway in BAT through inhibition of AMPK activity."
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"A key role of LKB1 is to negatively regulate the activity of mTOR complex 1 (mTORC1)."
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"To assess whether the loss of LKB1 leads to mTOR dependent glucose addiction in breast cancer, we analyzed the glycolytic profile of NIC tumor cells in response to glucose availability."
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"In contrast, we found that only LKB1 deficient cells effectively suppressed mTOR signaling and induced PARP cleavage in response to erlotinib treatments, both in vitro and in vivo."
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"It is known that LKB1 negatively regulates mTOR through AMPK, while SRC positively regulates it through PI3K and AKT signaling [XREF_BIBR; XREF_BIBR]."
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"LKB1 and AMPK axis activation is known to downregulate mTOR signaling under conditions of nutrient deprivation [XREF_BIBR, XREF_BIBR]."
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"In non small cell lung cancer cells, LKB1 and AMPK signaling negatively regulates mTOR activity and contributes to cell growth inhibition in response to energy stress."
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"Moreover, the tumor suppressor LKB1 negatively regulates the mTOR axis."
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"This is also consistent with our observation that LKB1 and AMPK upregulation failed to block mTOR signaling."
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"STK11 encodes a serine/threonine kinase called LKB1 that activates AMPK and negatively regulates the mTOR pathway in response to changes in cellular energy levels."
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"STK11 ( LKB1 ) inhibited mTOR signaling ."
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"Furthermore, hLKB1 DeltaLB C430A is no longer able to inhibit mTOR (as estimated by phosphorylation of p70-S6-Kinase 1, pS6K, XREF_FIG)."
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"Liver kinase B1 (LKB1), a regulator of AMP activated protein kinase (AMPK), mammalian target of rapamycin complex 1 (mTORC1) and FOXO pathways, links sensing and metabolism and is required for maintaining energy homeostasis."
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"Because LKB1 and AMPK signaling inhibits mTOR, but activated Akt stimulates mTOR activity, LKB1 and Akt are thought to play opposing roles with regard to mTOR regulation."
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"Pten and Lkb1 have been revealed as potent tumor suppressors of endometrial cancer in experimental mouse models, both of which also converge on and negatively regulate mTOR signaling."
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"In order to more rigorously examine the requirement of AMPK for LKB1 mediated inhibition of mTOR signaling, we introduced wild-type LKB1 into HeLa cells with or without two different dominant negative[MISSING/INVALID CREDENTIALS: limited to 200 char for Elsevier]"
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"Additionally, HeLa cells are defective in the tumor suppressor LKB1, which inhibits mTOR via TSC2 stimulation."
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"In contrast, states of energy or nutrient deprivation may trigger other upstream pathways, such as the LKB1 and AMPK pathway, which ultimately inhibits mTOR activity and limits cell growth and metabolism."
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"LKB1 tumour-suppressor activity is caused partly by AMPK-mediated inhibition of inappropriate mTOR activation."
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"Furthermore, erlotinib selectively blocked mammalian target of rapamycin signaling, inhibited cell growth and activated apoptosis in LKB1 deficient cells."
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"As LKB1 indirectly suppresses mTOR signalling via AMPK, LKB1 deletion increases mTOR signalling, as does mutant PIK3CA via AKT signalling."
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"STK11 also negatively regulates mammalian target of rapamycin (mTOR) signaling through its substrate AMPK, and the loss of STK11 leads to the aberrant activation of mTOR in a variety of tissues, with a case study showing usefulness of the mTor inhibitor everolimus for therapy (5-6) (Figure 1)."
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"The mTOR signaling is negatively regulated by LKB1 (liver kinase B1) and its downstream target AMP activated protein kinase (AMPK), two master nutrient sensors, that sense cellular stress (e.g., limiting ATP levels) and promote FAO in CD8 T cell memory and Treg cells (XREF_FIG) [XREF_BIBR], [XREF_BIBR]."
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"It is thought that MET in culture conditions with high concentrations of glucose stimulates AMPK through an LKB1-dependent mechanism, which blocks mTOR, causing a powerful inhibition of cell proliferation in several types of cancer cells specially non-TN breast cancer cells (21, 25, 26)."
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"In our model the combined deletion of both Lkb1 and Pten in the mouse bladder drastically activates mTOR pathway and this precise activation serves as a signal for EMT program execution (XREF_FIG)."
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"The LKB1 and AMPK signaling negatively regulates mTOR signaling."
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"LKB1 was found to negatively regulate the activities of mTOR, FAK and Src, and YAP1, and LKB1-mutant cells may become dependent on the hyper-activation of these signaling pathways."
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"Loss of LKB1 activates the mTOR pathway and promotes cell growth, survival and tumorigenesis in acute myeloid leukemia, squamous cell carcinoma of skin, and squamous cell carcinoma of lung via LKB1 and AMPK regulation [XREF_BIBR - XREF_BIBR]."
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"Second, in HeLa and pMEP4-LKB 1 inducible cells, induction of LKB1 decreased the activation of mTOR (phospho-mTOR, XREF_FIG, XREF_SUPPLEMENTARY) while enhancing the activation of AMP activated protein kinase (AMPK) as reflected by an increase in the phosphorylation of acetyl-CoA carboxylase (ACC), a substrate of the LKB1-AMPK cascade (XREF_FIG)."
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"In summary, LKB1 negatively regulates mTOR signaling through its substrate AMPK, and the loss of LKB1 leads to the aberrant activation of mTOR in a variety of tissues."
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"STK11 inhibits mTOR directly via alteration of the TSC1–TSC2 complex upstream of mTOR."
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"STK11 inhibits mTOR signaling through activation of AMPK , and in cancer cells with loss of AMPK activity , mTOR becomes an oncogenic driver46 ."
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"Considering the finding that LKB1 negatively regulates mTOR through AMPK and TSC2 [XREF_BIBR], all these observations suggest that mTOR inhibitors may suppress PJS associated cancers in addition to Peutz-Jeghers polyposis."
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"As expected, the loss of both Lkb1 and Pten in these tumors activated the AKT and mTOR pathways, likely driving cellular proliferation and tumorigenesis."
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"Thus, Lkb1, a multifunctional nutrient sensing kinase, is required to maintain HSC quiescence under reduced nutrient conditions and loss of Lkb1 promotes lineage commitment and HSC exhaustion in an mTOR independent manner XREF_BIBR - XREF_BIBR."
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"It has been reported in a variety of tissues that the inhibition of LKB1 signaling induced the aberrant activation of the mTOR signaling pathway."
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"STK11 inhibits mTOR signaling through activation of AMPK, and in cancer cells with loss of AMPK activity, mTOR becomes an oncogenic driver ."
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"PTEN and LKB1 loss synergistically enhances the activation of AKT and mTOR pathway, promotes the proliferation of pNET cell lines and confers the attenuated sensitivity of pNET cells to mTOR inhibitors."
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"In a mouse model of bladder cancer, Shorning et al. demonstrated that loss of LKB1 (upstream kinase of AMPKalpha) and PTEN synergizes to activate AMPK and mTOR and that rapamycin treatment reduced tumor burden in mice XREF_BIBR."
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"In non-small cell lung cancer, the LKB1/AMPK axis suppresses mTOR activity and promotes cell growth inhibition [51]."
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"For example, activation of the LKB1 and AMPK pathway inhibits mTOR in an Akt independent manner."
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"Interestingly, mTOR related gene sets had similar expression levels in STK11 ex1-2 and STK11 ex3-9, confirming that both types of tumor share the loss of STK11 tumor suppressor activity and subsequent activation of the mTOR pathway."
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"AMPK is also a central mediator of liver kinase B1, which inhibits mTOR."
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"Through inhibition of glucose uptake, EGFR TKI triggered AMPK activation in an LKB1 dependent manner due to the reduction of ATP level to suppress mTOR signaling and tumor growth."
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"To investigate the mechanisms underlying LKB1-deletion-caused follicular over-activation, we first focused on the mTOR pathway, which balances cell growth with energy control and is also negatively regulated by LKB1 through AMPK."
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"MTOR signaling, which is also inhibited by LKB1, remains upregulated in BCCs."
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