AMPK Phosphorylation of Raptor Mediates a Metabolic Checkpoint

Gwinn, Dana M.; Shackelford, David B.; Egan, Daniel F.; Mihaylova, Maria M.; Méry, Annabelle; Vasquez, Debbie S.; Turk, Benjamin E.; Shaw, Reuben J.

doi:10.1016/j.molcel.2008.03.003

Cited by 3,178 publications

(2,711 citation statements)

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“…The mechanism that leads to mTOR inactivation on glucose withdrawal is still incompletely characterized. It was first demonstrated to be AMPK dependent, but recently it has been reported that agents that reduce ATP levels can inactivate mTOR in the absence of AMPK (Gwinn et al, 2008;Kalender et al, 2010). Besides ATP levels, other good indicators of low glucose availability and energy stress are a decrease in the NADH/NAD þ ratio and a general decrease in protein acetylation.…”

Section: Sensing Glucose Deprivationmentioning

confidence: 99%

Sugar-free approaches to cancer cell killing

et al. 2010

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Tumors show an increased rate of glucose uptake and utilization. For this reason, glucose analogs are used to visualize tumors by the positron emission tomography technique, and inhibitors of glycolytic metabolism are being tested in clinical trials. Upregulation of glycolysis confers several advantages to tumor cells: it promotes tumor growth and has also been shown to interfere with cell death at multiple levels. Enforcement of glycolysis inhibits apoptosis induced by cytokine deprivation. Conversely, antiglycolytic agents enhance cell death induced by radio-and chemotherapy. Synergistic effects are likely due to regulation of the apoptotic machinery, as glucose regulates activation and levels of proapoptotic BH3-only proteins such as Bim, Bad, Puma and Noxa, as well as the antiapoptotic Bcl-2 family of proteins. Moreover, inhibition of glucose metabolism sensitizes cells to death ligands. Glucose deprivation and antiglycolytic drugs induce tumor cell death, which can proceed through necrosis or through mitochondrial or caspase-8-mediated apoptosis. We will discuss how oncogenic pathways involved in metabolic stress signaling, such as p53, AMPK (adenosine monophosphate-activated protein kinase) and Akt/mTOR (mammalian target of rapamycin), influence sensitivity to inhibition of glucose metabolism. Finally, we will analyze the rationale for the use of antiglycolytic inhibitors in the clinic, either as single agents or as a part of combination therapies.

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Section: Sensing Glucose Deprivationmentioning

confidence: 99%

Sugar-free approaches to cancer cell killing

et al. 2010

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“…Furthermore, mTORC1 activity can be affected by direct phosphorylation of its components by several kinases that also directly phosphorylate TSC1:TSC2. For example, direct phosphorylation of mTOR by PKB, and of raptor by AMPK have been shown to regulate mTORC1 activity (Figure 4) (Vander Haar et al, 2007;Gwinn et al, 2008).…”

Section: Maf1 Poliiimentioning

confidence: 99%

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

et al. 2011

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The liver kinase B1 (LKB1)/adenosine mono-phosphateactivated protein kinase (AMPK)/tuberous sclerosis complex (TSC)/mammalian target of rapamycin (mTOR) complex (mTORC1) cassette constitutes a canonical signaling pathway that integrates information on the metabolic and nutrient status and translates this into regulation of cell growth. Alterations in this pathway are associated with a wide variety of cancers and hereditary hamartoma syndromes, diseases in which hyperactivation of mTORC1 has been described. Specific mTORC1 inhibitors have been developed for clinical use, and these drugs have been anticipated to provide efficient treatment for these diseases. In the present review, we provide an overview of the metabolic LKB1/AMPK/TSC/mTORC1 pathway, describe how its aberrant signaling associates with cancer development, and indicate the difficulties encountered when biochemical data are extrapolated to provide avenues for rational treatment of disease when targeting this signaling pathway. A careful examination of preclinical and clinical studies performed with rapamycin or derivatives thereof shows that although results are encouraging, we are only half way in the long and winding road to design rationale treatment targeted at the LKB1/ AMPK/TSC/mTORC1 pathway. Inherited cancer syndromes associated with this pathway such as the PeutzJeghers syndrome and TSC, provide perfect models to study the relationship between genetics and disease phenotype, and to delineate the complexities that underlie translation of biochemical and genetical information to clinical management, and thus provide important clues for devising novel rational medicine for cancerous diseases in general.

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“…LKB1 is the major upstream kinase that phosphorylates and activates AMPK (Shaw et al, 2004b); activated AMPK phosphorylates a number of proteins resulting in a decrease in ATP-consuming processes and an increase in ATP production through inhibition of protein synthesis, fatty acid and glucose metabolism and enhancement of glucose transport (Hardie, 2007). AMPK turns off mTOR (mammalian target of rapamycin) by signaling to the tuberous sclerosis (TSC2/TSC1) tumor suppressor complex, as well by directly phosphorylating the mTOR-binding partner, raptor (regulatory associated protein of mTOR) (Corradetti et al, 2004;Shaw et al, 2004a;Gwinn et al, 2008). TSC2/TSC1, in response, inactivates the small GTPase Rheb (Ras homology enriched in brain), which positively signals to mTOR.…”

Section: Biochemical Functions Of Lkb1mentioning

confidence: 99%

LKB1; linking cell structure and tumor suppression

2008

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Germ line mutations in the LKB1 tumor suppressor gene are associated with the Peutz-Jeghers polyposis and cancer syndrome. Somatic mutations in Lkb1 are observed in sporadic pulmonary, pancreatic and biliary cancers and melanomas. The LKB1 serine-threonine kinase functionally and biochemically links control of cellular structure and energy utilization through activation of the AMPK family of kinases. Lkb1 regulates cell polarity through downstream kinases including AMPKs, MARKs and BRSKs, and nutrient utilization and cellular metabolism through the AMPK-mTOR pathway. LKB1 has been shown to affect normal chromosomal segregation, TGF-b signaling in the mesenchyme and WNT and p53 activity. Although each of the LKB1-dependent processes and downstream pathways have been individually delineated through work across a range of experimental systems, how they relate to Lkb1's role as a tumor suppressor remains to be fully explored and elucidated. The recent development of mouse cancer models harboring engineered mutations in Lkb1 have offered insights into how LKB1 may be functioning to restrain tumorigenesis and how its role as a master regulator of polarity and metabolism could contribute to its tumor suppressor function.

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AMPK Phosphorylation of Raptor Mediates a Metabolic Checkpoint

Cited by 3,178 publications

References 51 publications

Sugar-free approaches to cancer cell killing

Sugar-free approaches to cancer cell killing

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

LKB1; linking cell structure and tumor suppression

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