LKB1-Dependent Signaling Pathways

Alessi, Dario R.; Sakamoto, Kei; Bayascas, José R.

doi:10.1146/annurev.biochem.75.103004.142702

Cited by 699 publications

(752 citation statements)

References 130 publications

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“…Inhibition of mTOR in response to low intracellular energy levels is mediated by AMP-activated kinase (AMPK) and its activator, the protein kinase LKB1 [18]. Under conditions in which intracellular ATP is depleted and the level of AMP is increased, AMP binds to AMPK and allows LKB1 to phosphorylate Thr172 on the catalytic α subunit to activate AMPK [19].…”

Section: Mtor Signal Transduction and Cellular Functionsmentioning

confidence: 99%

Rapamycin and mTOR kinase inhibitors

2008

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Mammalian target of rapamycin (mTOR) is a protein kinase that controls cell growth, proliferation, and survival. mTOR signaling is often upregulated in cancer and there is great interest in developing drugs that target this enzyme. Rapamycin and its analogs bind to a domain separate from the catalytic site to block a subset of mTOR functions. These drugs are extremely selective for mTOR and are already in clinical use for treating cancers, but they could potentially activate an mTOR-dependent survival pathway that could lead to treatment failure. By contrast, small molecules that compete with ATP in the catalytic site would inhibit all of the kinase-dependent functions of mTOR without activating the survival pathway. Several non-selective mTOR kinase inhibitors have been described and here we review their chemical and cellular properties. Further development of selective mTOR kinase inhibitors holds the promise of yielding potent anticancer drugs with a novel mechanism of action.

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Section: Mtor Signal Transduction and Cellular Functionsmentioning

confidence: 99%

Rapamycin and mTOR kinase inhibitors

2008

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“…Additional AMPK-related kinases include the salt-inducible kinase 2 that regulates the cAMP response element-binding protein pathway and the less characterized NUAK1 and 2, QSK and SNRK, which appear to have functions in metabolism and stress responses (Screaton et al, 2004;Alessi et al, 2006).…”

Section: Biochemical Functions Of Lkb1mentioning

confidence: 99%

“…Together with the pseudokinase, STE20-related adaptor protein (STRAD), and the scaffolding protein, mouse protein 25 (MO25), LKB1 positively regulates the activity of at least 14 downstream kinases-related to the AMP-activated protein kinase (AMPK)-that are involved in the regulation of cellular responses to energy stress and the establishment of cell polarity (Baas et al, 2004b;Alessi et al, 2006;Katajisto et al, 2007). LKB1 can also phosphorylate other substrates including STRAD and phosphatase and tensin homolog (PTEN), although the biological significance of these modifications has not been established.…”

Section: Introductionmentioning

confidence: 99%

“…Despite the extensive characterization of its biochemical properties, iteration of downstream pathways and evaluation in a number of biological systems, the LKB1 tumor suppressor activity has yet to be conclusively ascribed to one of-or combinations of-its established functions. LKB1 has been the focus of a number of excellent reviews (Baas et al, 2004b;Alessi et al, 2006;Forcet and Billaud, 2007;Katajisto et al, 2007;Williams and Brenman, 2008). Below we discuss the relationships between LKB1 and cancer.…”

Section: Introductionmentioning

confidence: 99%

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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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“…When, due to either excessive ATP consumption or in the case of hypoxia, reduced aerobic ATP production, cellular AMP/ATP ratios are increased ( Figure 2). This is sensed by AMPK, which through binding of AMP undergoes a conformational change, upon which it can be phosphorylated by LKB1 (Figure 2) (Alessi et al, 2006;Hardie, 2007;Jansen et al, 2009). AMPKa can also be phosphorylated by calcium/calmodulin-dependent protein kinase kinase, which is triggered through influx of calcium ( Figure 2) (Hawley et al, 1995).…”

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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-Dependent Signaling Pathways

Cited by 699 publications

References 130 publications

Rapamycin and mTOR kinase inhibitors

Rapamycin and mTOR kinase inhibitors

LKB1; linking cell structure and tumor suppression

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

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